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1. A comprehensive assessment of demographic, environmental, and host genetic associations with gut microbiome diversity in healthy individuals

Author: Christian Hammer, Lluis Quintana-Murci, Allyson L. Byrd, Jacques Fellay, Cécile Alanio, Petar Scepanovic, Valentin Partula, Mathilde Touvier, Olivier Lantz, Stanislas Mondot, Jacob Bergstedt, Etienne Patin, Darragh Duffy, Matthew L. Albert, Flavia Hodel, Ecole Polytechnique Fédérale de Lausanne (EPFL), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Genentech, Inc. [San Francisco], Perelman School of Medicine, University of Pennsylvania [Philadelphia], Lund University [Lund], Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Swiss Institute of Bioinformatics [Genève] (SIB), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), This work benefited from the support of the French government’s Invest in the Future Program, managed by the Agence Nationale de la Recherche (ANR, reference 10-LABX-69-01). It was also supported by a grant from the Swiss National Science Foundation (31003A_175603 to JF)., We would like to thank to all the donors for their contribution to the study. The Milieu Intérieur Consortium is composed of the following team leaders: Laurent Abel (Hôpital Necker, Paris, France), Andres Alcover (Institut Pasteur, Paris, France), Hugues Aschard (Institut Pasteur, Paris, France), Kalla Astrom (Lund University, Lund, Sweden), Philippe Bousso (Institut Pasteur, Paris, France), Pierre Bruhns (Institut Pasteur, Paris, France), Ana Cumano (Institut Pasteur, Paris, France), Caroline Demangel (Institut Pasteur, Paris, France), Ludovic Deriano (Institut Pasteur, Paris, France), James Di Santo (Institut Pasteur, Paris, France), Françoise Dromer (Institut Pasteur, Paris, France), Darragh Duffy (Institut Pasteur, Paris, France), Gérard Eberl (Institut Pasteur, Paris, France), Jost Enninga (Institut Pasteur, Paris, France), Jacques Fellay (EPFL, Lausanne, Switzerland), Odile Gelpi (Institut Pasteur, Paris, France), Ivo Gomperts-Boneca (Institut Pasteur, Paris, France), Milena Hasan (Institut Pasteur, Paris, France), Serge Hercberg (Université Paris 13, Paris, France), Olivier Lantz (Institut Curie, Paris, France), Claude Leclerc (Institut Pasteur, Paris, France), Hugo Mouquet (Institut Pasteur, Paris, France), Sandra Pellegrini (Institut Pasteur, Paris, France), Stanislas Pol (Hôpital Côchin, Paris, France), Antonio Rausell (INSERM UMR 1163 – Institut Imagine, Paris, France), Lars Rogge (Institut Pasteur, Paris, France), Anavaj Sakuntabhai (Institut Pasteur, Paris, France), Olivier Schwartz (Institut Pasteur, Paris, France), Benno Schwikowski (Institut Pasteur, Paris, France), Spencer Shorte (Institut Pasteur, Paris, France), Vassili Soumelis (Institut Curie, Paris, France), Frédéric Tangy (Institut Pasteur, Paris, France), Eric Tartour (Hôpital Européen George Pompidou, Paris, France), Antoine Toubert (Hôpital Saint-Louis, Paris, France), Mathilde Touvier (Université Paris 13, Paris, France), Marie-Noëlle Ungeheuer (Institut Pasteur, Paris, France), Matthew L. Albert (Roche Genentech, South San Francisco, CA, USA), and Lluis Quintana-Murci (Institut Pasteur, Paris, France). Matthew L. Albert and Lluis Quintana-Murci are the co-coordinators of the consortium. Additional information can be found at http://www.milieuinterieur.fr/en., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Vougny, Marie-Christine, Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID, Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Pennsylvania, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Collège de France - Chaire Génomique humaine et évolution, Collège de France (CdF (institution)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC), Institut Curie-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR: 10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Fellay, Jacques [0000-0002-8240-939X], Apollo - University of Cambridge Repository, and Fellay, Jacques
Subjects: Male, population-structure, imputation, Genome-wide association study, dna, Cohort Studies, Feces, 0302 clinical medicine, GWAS, Gut, 16S rRNA gene sequencing, media_common, milieu-interieur, 0303 health sciences, dynamics, Genomics, Middle Aged, Healthy Volunteers, 3. Good health, 030220 oncology & carcinogenesis, Cohort, Medical genetics, lcsh:QR100-130, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Demographics, Sex ratio, Human, Adult, Microbiology (medical), medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, media_common.quotation_subject, Single-nucleotide polymorphism, Biology, Environment, Microbiology, lcsh:Microbial ecology, Young Adult, 03 medical and health sciences, Genetic variation, medicine, Humans, Microbiome, genome, Life Style, Aged, Demography, 030304 developmental biology, inference, Healthy, Bacteria, Host (biology), Research, Gastrointestinal Microbiome, extraction, 030217 neurology & neurosurgery, Imputation (genetics), Diversity (politics)
Abstract: Background The gut microbiome is an important determinant of human health. Its composition has been shown to be influenced by multiple environmental factors and likely by host genetic variation. In the framework of the Milieu Intérieur Consortium, a total of 1000 healthy individuals of western European ancestry, with a 1:1 sex ratio and evenly stratified across five decades of life (age 20–69), were recruited. We generated 16S ribosomal RNA profiles from stool samples for 858 participants. We investigated genetic and non-genetic factors that contribute to individual differences in fecal microbiome composition. Results Among 110 demographic, clinical, and environmental factors, 11 were identified as significantly correlated with α-diversity, ß-diversity, or abundance of specific microbial communities in multivariable models. Age and blood alanine aminotransferase levels showed the strongest associations with microbiome diversity. In total, all non-genetic factors explained 16.4% of the variance. We then searched for associations between > 5 million single nucleotide polymorphisms and the same indicators of fecal microbiome diversity, including the significant non-genetic factors as covariates. No genome-wide significant associations were identified after correction for multiple testing. A small fraction of previously reported associations between human genetic variants and specific taxa could be replicated in our cohort, while no replication was observed for any of the diversity metrics. Conclusion In a well-characterized cohort of healthy individuals, we identified several non-genetic variables associated with fecal microbiome diversity. In contrast, host genetics only had a negligible influence. Demographic and environmental factors are thus the main contributors to fecal microbiome composition in healthy individuals. Trial registration ClinicalTrials.gov identifier NCT01699893
Published: 2019

2. Safety of sitagliptin in treatment of hepatocellular carcinoma in chronic liver disease patients

Author: Vincent Bondet, Eric Savier, Olivier Scatton, Clémence Hollande, Matthew L. Albert, Jeremy Boussier, Stanislas Pol, Alba Llibre, Vincent Mallet, Estelle Mottez, Tan Phuc Buivan, Bruno Charbit, Frédéric Charlotte, Darragh Duffy, Université Paris Cité (UPCité), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hépatologie médicale [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Anatomie et cytologie pathologiques = Service de Pathologie [CHU Pitié-Salpêtrière] (ACP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Chirurgie Digestive, Hépato-Bilio-pancréatique et Transplantation Hépatique [CHU Pitié-Salpétrière], Fondation ARC pour la Recherche sur le Cancer, BONDET, Vincent, Université de Paris (UP), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et cytologie pathologiques [CHU Pitié-Salpêtrière] (ACP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: medicine.medical_specialty, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Population, Pharmaceutical Science, Chronic liver disease, Gastroenterology, sitagliptin, 03 medical and health sciences, 0302 clinical medicine, dipeptidyl peptidase 4, Internal medicine, medicine, Pharmacology (medical), neoadjuvant therapy, education, Adverse effect, Neoadjuvant therapy, Dipeptidyl peptidase-4, 030304 developmental biology, 0303 health sciences, education.field_of_study, business.industry, hepatocellular carcinoma, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], Complementary and alternative medicine, 030220 oncology & carcinogenesis, Sitagliptin, Hepatocellular carcinoma, business, Adjuvant, leucocyte trafficking, medicine.drug
Abstract: International audience; Background & Aims : Systemic therapies for hepatocellular carcinoma (HCC) treatment have limited efficacy and poor safety. Dipeptidyl peptidase-4 inhibitors were initially developed and approved as treatment for type 2 diabetes, yet oral administration of sitagliptin has recently been shown to improve naturally occurring tumour immunity in animal models of HCC.Methods : We conducted a phase Ib clinical trial to evaluate the impact of a pre-operative 3-week DPP4 inhibitor (sitagliptin) treatment in HCC patients undergoing liver resection. The primary objective was to evaluate the safety of a sitagliptin treatment in each of the three groups of patients, according to an escalating dosage of sitagliptin (100, 200 and 600 mg/d). Secondary objectives included the assessment of DPP4 activity, cytokine expression in plasma samples and circulating immune populations.Results : Fourteen patients were included and analysed. In all three dose groups, no severe adverse event related to sitagliptin was reported. A significant inhibition of DPP4 activity was observed upon sitagliptin treatment, which prevented the N-terminal truncation of CXCL10, leading to a mobilization of circulating CD8+ T cells and eosinophils. Immunochemistry analysis showed a lymphoid infiltration in all tumour samples with the presence of a population of CXCR3+ T cells in all but one of the tumours. Positivity for CXCL10 (IP10) and CCR3 in tumour and/or stroma cells was found in all resection pieces.Conclusion : In summary, sitagliptin can be used safely in patients with chronic liver disease and HCC, and could be tested in phase 2 trial, as an adjuvant in combination with others drugs, for the treatment of HCC patients.
Published: 2021

3. Accurate prediction of cell composition, age, smoking consumption and infection serostatus based on blood DNA methylation profiles

Author: Lluis Quintana-Murci, Darragh Duffy, Matthew L. Albert, Etienne Patin, Jacob Bergstedt, Alejandra Urrutia, Lund University [Lund], Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Genentech, Inc. [San Francisco], Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), This work benefited from support of the French government’s Program In vestissement d’Avenir, managed by the Agence Nationale de la Recherche (ANR, reference 10-LABX-69-01). J.B. is a member of the LCCC Linnaeus Center and the ELLIIT Excellence Center at Lund University and is supported by the ELLIIT Excellence Center., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Institut Pasteur [Paris], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: Regulation of gene expression, 0303 health sciences, Cellular differentiation, Genomics, Methylation, Computational biology, Biology, 01 natural sciences, 3. Good health, Predictive medicine, 010104 statistics & probability, 03 medical and health sciences, DNA methylation, [SDV.IMM]Life Sciences [q-bio]/Immunology, Epigenetics, 0101 mathematics, 030304 developmental biology, Epigenomics
Abstract: Posté sur bioRxiv le 30/10/2018; DNA methylation is a stable epigenetic alteration that plays a key role in cellular differentiation and gene regulation, and that has been proposed to mediate environmental effects on disease risk. Epigenome-wide association studies have identified and replicated associations between methylation sites and several disease conditions, which could serve as biomarkers in predictive medicine and forensics. Nevertheless, heterogeneity in cellular proportions between the compared groups could complicate interpretation. Reference-based cell-type deconvolution methods have proven useful in correcting epigenomic studies for cellular heterogeneity, but they rely on reference libraries of sorted cells and only predict a limited number of cell populations. Here we leverage >850,000 methylation sites included in the MethylationEPIC array and use elastic net regularized and stability selected regression models to predict the circulating levels of 70 blood cell subsets, measured by standardized flow cytometry in 962 healthy donors of western European descent. We show that our predictions, based on a hundred of methylation sites or lower, are less error-prone than other existing methods, and extend the number of cell types that can be accurately predicted. Application of the same methods to age, smoking consumption and several serological responses to pathogen antigens also provide accurate estimations. Together, our study substantially improves predictions of blood cell composition based on methylation profiles, which will be critical in the emerging field of medical epigenomics.
Published: 2021

4. Natural variation in the parameters of innate immune cells is preferentially driven by genetic factors

Author: Petar Scepanovic, Julie Hunkapiller, Jacob Bergstedt, Alejandra Urrutia, Jacques Fellay, Lluis Quintana-Murci, Hélène Quach, Friederike Jönsson, Cherie Green, Olivier Lantz, Lars Rogge, Stéphanie Thomas, Vincent Rouilly, Barbara Piasecka, Yoong Wearn Lim, Claire Leloup, Cécile Alanio, Isabelle Peguillet, Christian Hammer, Benoit Beitz, Magnus Fontes, Magge Zepeda, Matthew L. Albert, Valentina Libri, James P. Di Santo, Etienne Patin, Milena Hasan, François Huetz, Darragh Duffy, Vougny, Marie-Christine, Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Lund University [Lund], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ecole Polytechnique Fédérale de Lausanne (EPFL), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Anticorps en Thérapie et Pathologie, Genentech, Inc. [San Francisco], Immunorégulation, Biologie des Populations Lymphocytaires, Institut Curie [Paris], International Group for Data Analysis (IGDA), Immunité Innée - Innate Immunity, This work benefited from support of the French government’s program ‘Investissement d’Avenir’, managed by the Agence Nationale de la Recherche (reference 10-LABX-69-01). J.B. is a member of the LCCC Linnaeus Center and the ELLIIT Excellence Center at Lund University and is supported by the ELLIIT Excellence Center., The Milieu Intérieur Consortium : Laurent Abel, Andres Alcover, Kalle Astrom, Philippe Bousso, Pierre Bruhns, Ana Cumano, Caroline Demangel, Ludovic Deriano, James P. Di Santo, Françoise Dromer, Darragh Duffy, Gérard Eberl, Jost Enninga, Jacques Fellay, Antonio Freitas, Odile Gelpi, Ivo Gomperts Boneca, Serge Hercberg, Olivier Lantz, Claude Leclerc, Hugo Mouquet, Etienne Patin, Sandra Pellegrini, Stanislas Pol, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Vassili Soumelis, Frédéric Tangy, Eric Tartour, Antoine Toubert, Marie-Noëlle Ungeheuer, Lluís Quintana-Murci & Matthew L. Albert, ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lausanne (UNIL), and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]
Subjects: Adult, Male, 0301 basic medicine, MESH: Immunity, Innate/genetics, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Immunophenotyping, MESH: Genetic Variation/immunology, Immunology, Genome-wide association study, Disease, Adaptive Immunity, Biology, Immunophenotyping, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Immune system, Immunity, Genetic variation, Humans, Immunology and Allergy, Aged, Genetic association, MESH: Aged, Innate immune system, MESH: Humans, MESH: Middle Aged, Genetic Variation, MESH: Adult, Environmental exposure, Middle Aged, Immunity, Innate, MESH: Male, 3. Good health, 030104 developmental biology, MESH: Young Adult, MESH: Genome-Wide Association Study, MESH: Adaptive Immunity/genetics, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH: Female, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: A Publisher Correction to this article was published on 03 May 2018; International audience; The quantification and characterization of circulating immune cells provide key indicators of human health and disease. To identify the relative effects of environmental and genetic factors on variation in the parameters of innate and adaptive immune cells in homeostatic conditions, we combined standardized flow cytometry of blood leukocytes and genome-wide DNA genotyping of 1,000 healthy, unrelated people of Western European ancestry. We found that smoking, together with age, sex and latent infection with cytomegalovirus, were the main non-genetic factors that affected variation in parameters of human immune cells. Genome-wide association studies of 166 immunophenotypes identified 15 loci that showed enrichment for disease-associated variants. Finally, we demonstrated that the parameters of innate cells were more strongly controlled by genetic variation than were those of adaptive cells, which were driven by mainly environmental exposure. Our data establish a resource that will generate new hypotheses in immunology and highlight the role of innate immunity in susceptibility to common autoimmune diseases.
Published: 2018

5. Sex differences in IL-17 contribute to chronicity in male versus female urinary tract infection

Author: Darragh Duffy, Anna Zychlinsky Scharff, Matthew L. Albert, Livia Lacerda Mariano, Matthieu Rousseau, Tracy Canton, Magnus Fontes, Molly A. Ingersoll, Camila Rosat Consiglio, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), International Group for Data Analysis (IGDA), Institut Pasteur [Paris] (IP), Lund University [Lund], Rigshospitalet [Copenhagen], Copenhagen University Hospital, MAI was supported by funding from the European Union Seventh Framework Programme Marie Curie Action (PCIG11-GA- 2012-3221170) and the Agence Nationale de la Recherché (French National Research Agency) ANR-17-CE17-0014. LLM is part of the Pasteur-Paris University (PPU) International PhD Program, which received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 665807 and from the Labex Milieu Intérieur (ANR-10-LABX-69-01)., We gratefully acknowledge insightful discussions, technical support, and/or critical reading of the manuscript by Drs. Melanie Hamon, Lucy Glover, Jessica Quintin, Vincent Rouilly, Kimberly Kline, Nicolas Serafini, Clémence Hollande, and Björn Albrecht. We acknowledge the Labex Milieu Intérieur and the Technology Core of the Center for Translational Science at the Institut Pasteur for supporting aspects of this study. We thank Dr. Tim Sparwasser for sponsoring the research stay of AZS., ANR-17-CE17-0014,PredictUTI,Identification de biomarqueurs sanguins prédictifs des infections uriniaires récidivantes et développement d'immunothérapies préventives personnalisées(2017), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), European Project: 3221170,European Union Seventh Framework Programme Marie Curie Action, European Project: 665807,H2020,H2020-MSCA-COFUND-2014,PASTEURDOC(2015), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris], Vougny, Marie-Christine, Identification de biomarqueurs sanguins prédictifs des infections uriniaires récidivantes et développement d'immunothérapies préventives personnalisées - - PredictUTI2017 - ANR-17-CE17-0014 - AAPG2017 - VALID, Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID, 3221170 - European Union Seventh Framework Programme Marie Curie Action - 3221170 - INCOMING, and Institut Pasteur International Docotal Program - PASTEURDOC - - H20202015-10-01 - 2020-10-01 - 665807 - VALID
Subjects: 0301 basic medicine, Male, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.medical_treatment, Urinary system, Urinary Bladder, Immunology, Male mice, 03 medical and health sciences, Mice, 0302 clinical medicine, medicine, UTI/pyelonephritis, Animals, Uropathogenic Escherichia coli, Testosterone, Sex hormones, Lymphocytes, Escherichia coli Infections, Bacterial clearance, Mice, Knockout, Innate immunity, Sex Characteristics, Infectious disease, Innate immune system, Pyelonephritis, business.industry, Innate lymphoid cell, Interleukin-17, General Medicine, Immunity, Innate, 3. Good health, DNA-Binding Proteins, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Cytokine, Infectious disease (medical specialty), 030220 oncology & carcinogenesis, Urinary Tract Infections, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Interleukin 17, business, Research Article
Abstract: International audience; Sex-based differences influence incidence and outcome of infectious disease. Women have a significantly greater incidence of urinary tract infection (UTI) than men, yet, conversely, male UTI is more persistent with greater associated morbidity. Mechanisms underlying these sex-based differences are unknown, in part due to a lack of experimental models. We optimized a model to transurethrally infect male mice and directly compared UTI in both sexes. Although both sexes were initially equally colonized by uropathogenic E. coli, only male and testosterone-treated female mice remained chronically infected for up to 4 weeks. Female mice had more robust innate responses, including higher IL-17 expression, and increased γδ T cells and group 3 innate lymphoid cells in the bladder following infection. Accordingly, neutralizing IL-17 abolished resolution in female mice, identifying a cytokine pathway necessary for bacterial clearance. Our findings support the concept that sex-based responses to UTI contribute to impaired innate immunity in males and provide a rationale for non-antibiotic-based immune targeting to improve the response to UTI.
Published: 2019

6. Associations between usual diet and gut microbiota composition: results from the Milieu Intérieur cross-sectional study

Author: Camille Buscail, Pilar Galan, Lluis Quintana-Murci, Karen E. Assmann, Mélanie Deschasaux, Vincent Rouilly, Darragh Duffy, Emmanuelle Kesse-Guyot, Valentin Partula, Olivier Lantz, Mathilde Touvier, M. Torres, Matthew L. Albert, Chantal Julia, Paule Latino-Martel, Stéphanie Thomas, Stanislas Mondot, Serge Hercberg, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Santé publique France, Hôpital Avicenne, Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC), Centre de Recherche Translationnelle (CRT), Institut Pasteur [Paris], Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Evolutive Humaine - Human Evolutionary Genetics, Genentech, Inc. [San Francisco], Immunité et cancer (U932), Institut Curie-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie, Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Santé publique France - French National Public Health Agency [Saint-Maurice, France], Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Vougny, Marie-Christine, and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]
Subjects: 0301 basic medicine, Adult, Male, [SDV.IMM] Life Sciences [q-bio]/Immunology, Colon, Population, Medicine (miscellaneous), Gut flora, Diet Surveys, Food group, 03 medical and health sciences, Feces, Young Adult, Abundance (ecology), RNA, Ribosomal, 16S, Humans, Food science, Microbiome, education, Aged, 2. Zero hunger, education.field_of_study, Analysis of Variance, 030109 nutrition & dietetics, Nutrition and Dietetics, biology, Bacteria, gut microbiota, digestive, oral, and skin physiology, Feeding Behavior, Sequence Analysis, DNA, Middle Aged, biology.organism_classification, Diet, Gastrointestinal Microbiome, 030104 developmental biology, Cross-Sectional Studies, Diet, Western, Milieu Intérieur Consortium, Multivariate Analysis, usual diet, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, epidemiology, Omnivore, Analysis of variance, France, healthy population, Akkermansia muciniphila
Abstract: International audience; BACKGROUND:Diet is widely recognized as one of the main modifiable drivers of gut microbiota variability, and its influence on microbiota composition is an active area of investigation.OBJECTIVE:The present work aimed to explore the associations between usual diet and gut microbiota composition in a large sample of healthy French adults.METHODS:Gut microbiota composition was established through sequencing of the 16S rRNA gene in stool samples from 862 healthy French adults of the Milieu Intérieur study. Usual dietary consumptions were determined through the administration of a food-frequency questionnaire. The associations between dietary variables and α- and β-diversity indexes and relative taxa abundances were tested using Spearman correlations, permutational ANOVAs, and multivariate analyses with linear models, respectively.RESULTS:Foods generally considered as healthy (raw fruits, fish) were positively associated with α-diversity, whereas food items for which a limited consumption is generally recommended (fried products, sodas or sugary drinks, fatty sweet products, processed meats, ready-cooked meals, and desserts) were negatively associated with α-diversity. Fruits, fried products, ready-cooked meals, and cheese contributed to shifts within microbiota composition (β-diversity). Our results also highlighted a number of associations between various food group intakes and abundances of specific phyla, genera, and species. For instance, the consumption of cheese was negatively associated with Akkermansia muciniphila abundance.CONCLUSIONS:This large-scale population-based study supports that the usual consumption of certain food items is associated with several gut microbial features, and extends the mechanistic arguments linking Western diet to an altered microbiota composition. These results provide new insights into the understanding of complex diet-gut microbiota relations, and their implications for host health deserve further investigation because altered microbiota diversity was consistently linked to increased risk of several health outcomes. This trial was registered at clinicaltrials.gov as NCT01699893.
Published: 2019

7. Inhibition of the dipeptidyl peptidase DPP4 (CD26) reveals IL-33-dependent eosinophil-mediated control of tumor growth

Author: Clémence Hollande, Wendy Sandoval, Vincent Mallet, Tamaki Nozawa, Darragh Duffy, Vincent Bondet, Stanislas Pol, Jill Schartner, Valerie Paradis, James Ziai, Rosa Barreira da Silva, Gérard Eberl, Binfeng Lu, Matthew L. Albert, Jeremy Boussier, Wilson Phung, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Genentech, Inc. [San Francisco], University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris], Service d’Anatomie Pathologique [CHU Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hépatologie médicale [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Microenvironnement et Immunité - Microenvironment and Immunity, Funding for the work was provided by Fondation ARC pour la recherche sur le cancer, Institut national de la santé et de la recherche médicale (Inserm), Fondation pour la recherche médicale (FRM, FDM 40432) and LabEx Immuno-Onco (ANR)., Thanks to H. Saklani, M. A. Ingersoll and T. Canton for their help with mouse experimental work and ethical statement., ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris] (IP)
Subjects: 0301 basic medicine, Chemokine CCL11, Chemokine, Lymphocyte, Dipeptidyl Peptidase 4, Immunology, Dipeptidyl peptidase, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, Cell Line, Tumor, medicine, Immunology and Allergy, CXCL10, Animals, Humans, CCL11, Mice, Knockout, Dipeptidyl-Peptidase IV Inhibitors, Mice, Inbred BALB C, biology, Chemistry, Sitagliptin Phosphate, Degranulation, Neoplasms, Experimental, Eosinophil, Interleukin-33, 3. Good health, Interleukin 33, Eosinophils, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Cancer research, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, 030215 immunology
Abstract: Post-translational modification of chemokines mediated by the dipeptidyl peptidase DPP4 (CD26) has been shown to negatively regulate lymphocyte trafficking, and its inhibition enhances T cell migration and tumor immunity by preserving functional chemokine CXCL10. By extending those initial findings to pre-clinical models of hepatocellular carcinoma and breast cancer, we discovered a distinct mechanism by which inhibition of DPP4 improves anti-tumor responses. Administration of the DPP4 inhibitor sitagliptin resulted in higher concentrations of the chemokine CCL11 and increased migration of eosinophils into solid tumors. Enhanced tumor control was preserved in mice lacking lymphocytes and was ablated after depletion of eosinophils or treatment with degranulation inhibitors. We further demonstrated that tumor-cell expression of the alarmin IL-33 was necessary and sufficient for eosinophil-mediated anti-tumor responses and that this mechanism contributed to the efficacy of checkpoint-inhibitor therapy. These findings provide insight into IL-33- and eosinophil-mediated tumor control, revealed when endogenous mechanisms of DPP4 immunoregulation are inhibited. Eosinophils have been described mainly in allergy settings but are increasingly appreciated as being involved in other aspects of immunity. Albert and colleagues use a clinically approved inhibitor of the dipeptidyl peptidase DPP4 to facilitate the recruitment of eosinophils to mouse tumors, where they are essential in tumor destruction.
Published: 2019

8. Basophils from allergic patients are neither hyperresponsive to activation signals nor hyporesponsive to inhibition signals

Author: Tan-Phuc Buivan, Aurélie Cotillard, Matthew L. Albert, Estelle Mottez, Raphaëlle Bourdet-Sicard, Lydie Cassard, J. Laurent, Katia Sperber, Marc Daëron, M.T. Guinnepain, Centre d'Immunologie Humaine (CIH), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Soladis, Danone Research, Groupe DANONE, Centre Médical de l'Institut Pasteur, Institut Pasteur [Paris], Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Médical de l'Institut Pasteur (CMIP), Institut Pasteur [Paris] (IP), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0301 basic medicine, Allergy, FcεRI, medicine.disease_cause, Immunoglobulin E, chronic urticaria, 0302 clinical medicine, Allergen, Immunology and Allergy, Outpatient clinic, Receptor, biology, atopic dermatitis, hemic and immune systems, Lacticaseibacillus paracasei, Middle Aged, Basophils, 3. Good health, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Anaphylaxis, Adult, lactobacilli, Adolescent, Immunology, chemical and pharmacologic phenomena, Young Adult, 03 medical and health sciences, Immune system, rhinitis, parasitic diseases, Hypersensitivity, medicine, Humans, negative regulation, Aged, FcγRIIB, basophil activation, Receptors, IgE, business.industry, Receptors, IgG, asthma, medicine.disease, Basophil activation, 030104 developmental biology, biology.protein, business, 030215 immunology
Abstract: International audience; BACKGROUND:Basophil activation contributes to inflammatory reactions, especially in allergy. It is controlled, both positively and negatively, by several mechanisms. High-affinity IgE receptors (FcεRI) generate a mixture of activation and inhibition signals when aggregated, the ratio of which depends on the concentration of allergen recognized by receptor-bound IgE. Low-affinity IgG receptors (FcγRIIA/B) generate inhibition signals when coengaged with FcεRI by allergen-antibody immune complexes. Commensal and probiotic bacteria, such as Lactobacillus paracasei, generate inhibition signals through still unclear mechanisms.OBJECTIVE:We sought to investigate whether mechanisms that control, both positively and negatively, basophil activation, which were unraveled and studied in basophils from healthy donors, are functional in allergic patients.METHODS:FcεRI and FcγRIIA/B expression, FcεRI-dependent activation, FcεRI-dependent inhibition, and FcγRIIB-dependent inhibition were examined in blood basophils incubated overnight with or without L paracasei and challenged under 10 experimental conditions. Basophils from healthy donors were compared with basophils from patients who consulted an allergology outpatient clinic over a period of 3 months with respiratory allergy, anaphylaxis antecedents, chronic urticaria, and/or atopic dermatitis.RESULTS:Patients' basophils expressed neither more FcεRI nor less FcγRIIB than basophils from healthy donors. They were neither hyperreactive to positive regulation nor hyporeactive to negative regulation, irrespective of the receptors or mechanisms involved and the allergic manifestations of the patients.CONCLUSION:Regulatory mechanisms that control basophil activation are fully functional in allergic patients. Intrinsic defects in these mechanisms do not explain allergic manifestations. Based on these mechanisms, immune checkpoint modifiers can be developed as novel therapeutic tools for allergy.
Published: 2018

9. Human thymopoiesis is influenced by a common genetic variant within the TCRA-TCRD locus

Author: Lluis Quintana-Murci, Marine Germain, Magnus Fontes, Antoine Toubert, Itauá Leston Araujo, David-Alexandre Trégouët, James P. Di Santo, Emmanuel Clave, Corinne Douay, Silvia Lopez-Lastra, Milena Hasan, Bruno Charbit, Noémie Saut, Breno Luiz Melo-Lima, Darragh Duffy, Cécile Alanio, Jacob Bergstedt, Alejandra Urrutia, Cameron Ross MacPherson, Yan Li, Etienne Patin, Pierre-Emmanuel Morange, Matthew L. Albert, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Alloimmunité-Autoimmunité-Transplantation (A2T), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Lund University [Lund], Genentech, Inc., Genentech, Inc. [San Francisco], Immunité Innée - Innate Immunity, Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), International Group for Data Analysis (IGDA), Service d'Immunologie et d'Histocompatibilité, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by the French government’s Invest in the Future Program, managed by the Agence Nationale de la Recherche (ANR, 10-LABX-69-01). I.L.A. was a recipient of the Science without Borders PhD program from Brazil Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). J.B. is a member of the Lund Center for Control of Complex Engineering Systems (LCCC) Linnaeus Center and the Excellence Center at Linköping-Lund in Information Technology (ELLIT) Excellence Center at Lund University and is supported by the ELLIIT Excellence Center. J.P.D.S., Y.L., and S.L.-L. received funding from Institut Pasteur, INSERM, the Laboratoire d’Excellence REVIVE. A.T. and E.C. received funding from ANR grant PriCelAge (ANR-14-CE14-0030-01). Genetic investigations in the MARTHA study were supported by the GENMED Laboratory of Excellence on Medical Genomics (ANR-10-LABX-0013), We thank J. Fellay, P. Scepanovic, and C. A. W. Thorball for support with genetic analysis and J.-M. Doisne, G. M. Ranson, and H. Strick-Marchand for support with humanized mouse experiments. We thank V. Asnafi, E. Macintyre, A. Cieslak, and I. André-Schmutz for helpful discussions. We also thank the Centre d’Immunologie Humaine (Institut Pasteur, Paris, France) for support., ANR-14-CE14-0030,PriCelAge,Induction de réponses cellulaires T avec l'âge avancé(2014), ANR-10-LABX-0013,GENMED,Medical Genomics(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle (CRT), Institut Pasteur [Paris], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Immunité Innée, Centre recherche en CardioVasculaire et Nutrition (C2VN), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), ANR-14-CE14-0030,PriCelAge,Induction de réponses cellulaires T avec l’âge avancé(2014), ANR: PREFI-10-LABX-13/10-LABX-0013,GENMED,Medical Genomics(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, education.field_of_study, T-cell receptor excision circles, T cell, Population, Genome-wide association study, Locus (genetics), General Medicine, Biology, 3. Good health, Transplantation, 03 medical and health sciences, Haematopoiesis, Thymocyte, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, education
Abstract: International audience; The thymus is the primary lymphoid organ where naïve T cells are generated; however, with the exception of age, the parameters that govern its function in healthy humans remain unknown. We characterized the variability of thymic function among 1000 age- and sex-stratified healthy adults of the Milieu Intérieur cohort, using quantification of T cell receptor excision circles (TRECs) in peripheral blood T cells as a surrogate marker of thymopoiesis. Age and sex were the only nonheritable factors identified that affect thymic function. TREC amounts decreased with age and were higher in women compared to men. In addition, a genome-wide association study revealed a common variant (rs2204985) within the T cell receptor TCRA-TCRD locus, between the DD2 and DD3 gene segments, which associated with TREC amounts. Strikingly, transplantation of human hematopoietic stem cells with the rs2204985 GG genotype into immunodeficient mice led to thymopoiesis with higher TRECs, increased thymocyte counts, and a higher TCR repertoire diversity. Our population immunology approach revealed a genetic locus that influences thymopoiesis in healthy adults, with potentially broad implications in precision medicine.
Published: 2018

10. Systemic DPP4 activity is reduced during primary HIV-1 infection and is associated with intestinal RORC + CD4 + cell levels: a surrogate marker candidate of HIV-induced intestinal damage

Author: Yoann Madec, Michaela Müller-Trutwin, Nicolas Huot, Simon P. Jochems, Mathilde Ghislain, Roger Le Grand, Matthew L. Albert, Mirko Paiardini, Beatrice Jacquelin, Darragh Duffy, Faroudy Boufassa, Cécile Goujard, Thalia Garcia-Tellez, Luca Micci, Camille Lécuroux, Olivier Lambotte, Nicolas Noel, Laurence Meyer, Mickaël J.-Y. Ploquin, Neeltje A. Kootstra, Thijs Booiman, Armanda Casrouge, HIV, Inflammation et persistance - HIV, Inflammation and Persistence, Institut Pasteur [Paris] (IP), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Yerkes National Primate Research Center [Lawrenceville, GA], Emory University [Atlanta, GA], Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the ANRS and the Fondation l'Oréal. MJP was the recipient of a SIDACTION Young Investigator fellowship. SPJ received a PhD fellowship from the French Ministry of Higher Education and Research and TGT from the Pasteur Paris University International PhD program and Institut Carnot Microbes et Santé. NH received a postdoctoral fellowship from the French Vaccine Research Institute (Créteil, France), which is supported by the « Investissements d'Avenir program » managed by the National Agency of Research (ANR) under reference ANR‐10‐LABX‐77. The Center for Infectious Disease models and Innovative Therapies (IDMIT) is supported by the French government 'Programme d'Investissements d'Avenir' (PIA) under Grant ANR‐11‐INBS‐0008 funding the Infectious Disease Models and Innovative Therapies (IDMIT, Fontenay‐aux‐Roses, France) infrastructure, the PIA grant ANR‐10‐EQPX‐02‐01 funding the FlowCyTech facility (IDMIT, Fontenay‐aux‐Roses, France). This work was supported by the ANRS and also by the NIH under award numbers AI116379 (to MP) and by ORIP/OD P51OD011132 (formerly NCRR P51RR000165, to the YNPRC)., ANR-11-INBS-0008,IDMIT,Infrastructure nationale pour la modélisation des maladies infectieuses humaines(2011), ANR-10-EQPX-0002,FlowCyTech,Plateforme de phénotypage en Mass cytométrie pour l'analyse multiparamétrique de biomarqueurs complexes de l'efficacité de nouvelles stratégies thérapeutiques ou vaccinales(2010), APH - Aging & Later Life, AII - Infectious diseases, Experimental Immunology, HIV, Inflammation et persistance, Institut Pasteur [Paris], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université (HESAM)-HESAM Université (HESAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), and HESAM Université (HESAM)-HESAM Université (HESAM)
Subjects: CD4-Positive T-Lymphocytes, Male, 0301 basic medicine, Simian Acquired Immunodeficiency Syndrome, HIV Infections, 0302 clinical medicine, RAR-related orphan receptor gamma, Chlorocebus aethiops, 030212 general & internal medicine, Research Articles, virus diseases, Nuclear Receptor Subfamily 1, Group F, Member 3, 3. Good health, Infectious Diseases, medicine.anatomical_structure, SIV, Biomarker (medicine), biomarker, [SDV.IMM]Life Sciences [q-bio]/Immunology, Th17, medicine.symptom, Research Article, Adult, Dipeptidyl Peptidase 4, Rectum, Ileum, Inflammation, 03 medical and health sciences, Immune system, medicine, Animals, Humans, intestine, business.industry, Interleukins, Public Health, Environmental and Occupational Health, HIV, Small intestine, CD4 Lymphocyte Count, Intestinal Diseases, Chronic infection, 030104 developmental biology, inflammation, dipeptidylpeptidase, Immunology, HIV-1, Macaca, Th17 Cells, business, Biomarkers
Abstract: Introduction Combined anti‐retroviral therapy (cART) transformed HIV‐1 from a deadly disease into a chronic infection, but does not cure HIV infection. It also does not fully restore HIV‐induced gut damage unless administered extremely early after infection. Additional biomarkers are needed to evaluate the capacity of therapies aimed at HIV remission/cure to restore HIV‐induced intestinal immune damage and limit chronic inflammation. Herein, we aimed to identify a systemic surrogate marker whose levels would reflect gut immune damage such as intestinal Th17 cell loss starting from primary HIV‐1 infection. Methods Biomarker discovery approaches were performed in four independent cohorts, covering HIV‐1 primary and chronic infection in 496 naïve or cART‐treated patients (Amsterdam cohort (ACS), ANRS PRIMO, COPANA and CODEX cohorts). The concentration and activity of soluble Dipeptidylpeptidase 4 (sDPP4) were quantified in the blood from these patients, including pre‐ and post‐infection samples in the ACS cohort. For quantification of DPP4 in the gut, we utilized two non‐human primate models, representing pathogenic (macaque) and non‐pathogenic (African green monkey) SIV infection. Four gut compartments were analysed in each animal model (ileum, jejunum, colon and rectum) for quantification of DPP4,RORC and TBX21 gene expression in sorted CD4+ cells. To analyse if sDPP4 levels increase when Th17 cells were restored, we quantified sDPP4 in plasma from SIV‐infected macaques treated with IL‐21. Results We showed that sDPP4 levels were strongly decreased in primary HIV‐1 infection. Strikingly, sDPP4 levels in primary HIV‐1 infection predicted time to AIDS. They were not increased by cART in chronic HIV‐1 infection (median 36 months on cART). In the gut of SIV‐infected non‐human primates, DPP4 mRNA was higher in CD4+ than CD4− leucocytes. DPP4 specifically correlated with RORC expression, a Th17 marker, in CD4+ cells from the intestine. We further demonstrated that sDPP4 activity levels were increased in animals treated with IL‐21 and that this increase was associated with restoration of the Th17 compartment and reduced inflammation. Furthermore, DPP4 mRNA levels in small intestine CD4+ cells positively correlated with circulating DPP4 activity. Conclusion These data provide evidence that blood sDPP4 levels could be useful as a correlate for HIV‐induced intestinal damage.
Published: 2018

11. Plasmacytoid dendritic cells control dengue and Chikungunya virus infections via IRF7-regulated interferon responses

Author: Brian Webster, Scott W Werneke, Biljana Zafirova, Sébastien This, Séverin Coléon, Elodie Décembre, Helena Paidassi, Isabelle Bouvier, Pierre-Emmanuel Joubert, Darragh Duffy, Thierry Walzer, Matthew L Albert, Marlène Dreux, Trafic Vésiculaire, Réponse Innée et Virus – Vesicular trafficking, Innate response, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Genentech, Inc. [San Francisco], Lymphocytes B effecteurs et à mémoire – Effector and memory B cells, Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, This work was supported by grants from the ‘Agence Nationale pour la Recherche’ (ANR-JCJC-EXAMIN), the ‘‘Agence Nationale pour la Recherche contre le SIDA et les Hépatites Virales’’ (ANRS-AO 2016–01) and the LabEx Ecofect Grant ANR-11-LABX-0048 to MD, ANR-14-CE14-0015-02 CHIKV-Viro-Immuno to MLA. BW’s postdoctoral fellowship was sponsored by EMBO (ALTF 1466–2014). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript, We thank A Davidson (Bristol University) for providing the DENV-2 strain New Guinea C, P Despres (Pasteur Institut, Paris, France) for the anti-E DENV 3H5 antibody, V Lotteau (CIRI, Lyon, France) for Influenza A virus stocks, FV Chisari (Scripps Research Institute, La Jolla, CA) for the Huh-7.5.1 cells, T Taniguchi (University of Tokyo, Tokyo, Japan) for the Irf3/7 DKO mice, J Tschopp for the cardif-/- mice, and S Akira for the Tlr7-/- mice. We are grateful to Y Jaillais for critical reading of the manuscript, F Fusil for assistance with mice and to our colleagues for encouragement and help. We acknowledge the contribution of SFR Biosciences (UMS3444/CNRS, US8/Inserm, ENS de Lyon, UCBL) facilities, PBES and cytometry for mice housing and technical assistance., ANR-13-JSV3-0004,EXAMIN,Les Exosomes enrichis en ARN viraux sont Médiateurs de la réponse Interféron(2013), ANR-11-LABX-0048,ECOFECT,Dynamiques eco-évolutives des maladies infectieuses(2011), ANR-14-CE14-0015,CHIKV-Viro-Immuno,Multiplication et Relation avec l'hôte du virus Chikungunya(2014), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vougny, Marie-Christine, Jeunes Chercheuses et Jeunes Chercheurs - Les Exosomes enrichis en ARN viraux sont Médiateurs de la réponse Interféron - - EXAMIN2013 - ANR-13-JSV3-0004 - JC - VALID, Dynamiques eco-évolutives des maladies infectieuses - - ECOFECT2011 - ANR-11-LABX-0048 - LABX - VALID, and Appel à projets générique - Multiplication et Relation avec l'hôte du virus Chikungunya - - CHIKV-Viro-Immuno2014 - ANR-14-CE14-0015 - Appel à projets générique - VALID
Subjects: Male, [SDV.IMM] Life Sciences [q-bio]/Immunology, QH301-705.5, Science, Interferon Regulatory Factor-7, viruses, Dengue, immunology, Interferon-gamma, Mice, Animals, Humans, dendritic cells, human, Biology (General), mouse, Mice, Knockout, virus diseases, hemic and immune systems, Dengue Virus, Survival Analysis, virology, Killer Cells, Natural, Mice, Inbred C57BL, interferons, Disease Models, Animal, Gene Expression Regulation, inflammation, Host-Pathogen Interactions, Interferon Type I, Medicine, Chikungunya Fever, RNA, Viral, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Interferon Regulatory Factor-3, Chikungunya virus, Spleen, Signal Transduction
Abstract: International audience; Type I interferon (IFN-I) responses are critical for the control of RNA virus infections, however, many viruses, including Dengue (DENV) and Chikungunya (CHIKV) virus, do not directly activate plasmacytoid dendritic cells (pDCs), robust IFN-I producing cells. Herein, we demonstrated that DENV and CHIKV infected cells are sensed by pDCs, indirectly, resulting in selective IRF7 activation and IFN-I production, in the absence of other inflammatory cytokine responses. To elucidate pDC immunomodulatory functions, we developed a mouse model in which IRF7 signaling is restricted to pDC. Despite undetectable levels of IFN-I protein, pDC-restricted IRF7 signaling controlled both viruses and was sufficient to protect mice from lethal CHIKV infection. Early pDC IRF7-signaling resulted in amplification of downstream antiviral responses, including an accelerated natural killer (NK) cell-mediated type II IFN response. These studies revealed the dominant, yet indirect role of pDC IRF7-signaling in directing both type I and II IFN responses during arbovirus infections.
Published: 2018

12. Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges

Author: Barbara, Piasecka, Darragh, Duffy, Alejandra, Urrutia, Hélène, Quach, Etienne, Patin, Céline, Posseme, Jacob, Bergstedt, Bruno, Charbit, Vincent, Rouilly, Cameron R, MacPherson, Milena, Hasan, Benoit, Albaud, David, Gentien, Jacques, Fellay, Matthew L, Albert, Lluis, Quintana-Murci, Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris], Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Genentech, Inc., Genentech, Inc. [San Francisco], Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Lund University [Lund], International Group for Data Analysis (IGDA), Plateforme de génomique [Institut Curie], Institut Curie [Paris], Ecole Polytechnique Fédérale de Lausanne (EPFL), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL), This work was supported by the French Government’s Investissement d’Avenir Program, Laboratoire d’Excellence 'Milieu Intérieur' Grant ANR-10-LABX-69-01., We acknowledge Stephanie Thomas for managing the Milieu Intérieur Consortium. Milieu intérieur Consortium : Abel L, Alcover A, Aschard H, Aström K, Bousso P, Bruhns P, Cumano A, Duffy D, Demangel C, Deriano L, Di Santo J, Dromer F, Eberl G, Enninga J, Fellay J, Fontes M, Freitas A, Gelpi O, Gomperts-Boneca I, Hercberg S, Lantz O, Leclerc C, Mouquet H, Patin E, Pellegrini S, Pol S, Raussel A, Rogge L, Sakuntabhai A, Schwartz O, Schwikowski B, Shorte S, Soumelis V, Tangy F, Tartour E, Toubert A, Ungeheuer MN, Quintana-Murci L, Albert ML., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Centre de Recherche Translationnelle ( CRT ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Bioinformatique, Biostatistique et Biologie Intégrative ( C3BI ), International Group for Data Analysis ( IGDA ), Institut Curie, Ecole Polytechnique Fédérale de Lausanne ( EPFL ), Milieu intérieur Consortium : Abel L, Alcover A, Aschard H, Aström K, Bousso P, Bruhns P, Cumano A, Duffy D, Demangel C, Deriano L, Di Santo J, Dromer F, Eberl G, Enninga J, Fellay J, Fontes M, Freitas A, Gelpi O, Gomperts-Boneca I, Hercberg S, Lantz O, Leclerc C, Mouquet H, Patin E, Pellegrini S, Pol S, Raussel A, Rogge L, Sakuntabhai A, Schwartz O, Schwikowski B, Shorte S, Soumelis V, Tangy F, Tartour E, Toubert A, Ungeheuer MN, Quintana-Murci L, Albert ML., ANR : 10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE ( 2010 ), Vougny, Marie-Christine, Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID, Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lausanne = University of Lausanne (UNIL), Milieu Intérieur Consortium, Abel, L., Alcover, A., Aschard, H., Aström, K., Bousso, P., Bruhns, P., Cumano, A., Duffy, D., Demangel, C., Deriano, L., Di Santo, J., Dromer, F., Eberl, G., Enninga, J., Fellay, J., Fontes, M., Freitas, A., Gelpi, O., Gomperts-Boneca, I., Hercberg, S., Lantz, O., Leclerc, C., Mouquet, H., Patin, E., Pellegrini, S., Pol, S., Raussel, A., Rogge, L., Sakuntabhai, A., Schwartz, O., Schwikowski, B., Shorte, S., Soumelis, V., Tangy, F., Tartour, E., Toubert, A., Ungeheuer, M.N., Quintana-Murci, L., and Albert, M.L.
Subjects: Adult, Male, Aging, Genotype, [SDV.IMM] Life Sciences [q-bio]/Immunology, Quantitative Trait Loci, [ SDV.IMM.IA ] Life Sciences [q-bio]/Immunology/Adaptive immunology, Cohort Studies, Enterotoxins, Young Adult, Immunology and Inflammation, Humans, sex, genetics, [ SDV.BIBS ] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Aged, [ SDV.IMM.II ] Life Sciences [q-bio]/Immunology/Innate immunity, Bacteria, Fungi, Genetic Variation, Middle Aged, Biological Sciences, Bacteria/immunology, Enterotoxins/immunology, Female, Fungi/immunology, Gene Expression Regulation/immunology, Influenza A virus/immunology, age, gene expression, human immune variation, [ SDV.GEN.GPO ] Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Gene Expression Regulation, PNAS Plus, Influenza A virus, [SDV.IMM]Life Sciences [q-bio]/Immunology
Abstract: Significance Identifying the drivers of the interindividual diversity of the human immune system is crucial to understand their consequences on immune-mediated diseases. By examining the transcriptional responses of 1,000 individuals to various microbial challenges, we show that age and sex influence the expression of many immune-related genes, but their effects are overall moderate, whereas genetic factors affect a smaller gene set but with a stronger effect. We identify numerous genetic variants that affect transcriptional variation on infection, many of which are associated with autoimmune or inflammatory disorders. These results enable additional exploration of the role of regulatory variants in the pathogenesis of immune-related diseases and improve our understanding of the respective effects of age, sex, and genetics on immune response variation., The contribution of host genetic and nongenetic factors to immunological differences in humans remains largely undefined. Here, we generated bacterial-, fungal-, and viral-induced immune transcriptional profiles in an age- and sex-balanced cohort of 1,000 healthy individuals and searched for the determinants of immune response variation. We found that age and sex affected the transcriptional response of most immune-related genes, with age effects being more stimulus-specific relative to sex effects, which were largely shared across conditions. Although specific cell populations mediated the effects of age and sex on gene expression, including CD8+ T cells for age and CD4+ T cells and monocytes for sex, we detected a direct effect of these intrinsic factors for the majority of immune genes. The mapping of expression quantitative trait loci (eQTLs) revealed that genetic factors had a stronger effect on immune gene regulation than age and sex, yet they affected a smaller number of genes. Importantly, we identified numerous genetic variants that manifested their regulatory effects exclusively on immune stimulation, including a Candida albicans-specific master regulator at the CR1 locus. These response eQTLs were enriched in disease-associated variants, particularly for autoimmune and inflammatory disorders, indicating that differences in disease risk may result from regulatory variants exerting their effects only in the presence of immune stress. Together, this study quantifies the respective effects of age, sex, genetics, and cellular heterogeneity on the interindividual variability of immune responses and constitutes a valuable resource for further exploration in the context of different infection risks or disease outcomes.
Published: 2018

13. Study of the Humoral Immune Response towards HCV Genotype 4 Using a Bead-Based Multiplex Serological Assay

Author: Mohamed S. Abdel-Hamid, Darragh Duffy, Nicole Schneiderhan-Marra, Stanislas Pol, Angela Filomena, Arnaud Fontanet, Jens C. Göpfert, Matthew L. Albert, Thomas O. Joos, Gamal Esmat, Natural and Medical Sciences Institute [Reutlingen] (NMI), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hépatologie médicale [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Microbiology [Minia], Minia University, Department of Endemic Medicine and Hepatology, Cairo University, Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), This work was supported by the European Commission FP7 project SPHINX (grant referenceNo.: 261365). We thank Stephanie Thomas (Institut Pasteur/INSERM, France) for project management and EstelleMottez for clinical study support (Institut Pasteur/INSERM, France)., European Project: 261365,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,SPHINX(2010), Vougny, Marie-Christine, Spontaneous clearance in Patients acutely infected with HCV - Immune profiling, Novel biomarkers and X-omics approaches - SPHINX - - EC:FP7:HEALTH2010-11-01 - 2014-04-30 - 261365 - VALID, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), and Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM)
Subjects: 0301 basic medicine, [SDV.IMM] Life Sciences [q-bio]/Immunology, Hepatitis C virus, Biomedical Engineering, Bioengineering, medicine.disease_cause, Biochemistry, multiplex serological assay, Article, Serology, lcsh:Chemistry, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Antigen, Genotype, medicine, Multiplex, Seroconversion, lcsh:Science, lcsh:QH301-705.5, NS5B, ComputingMilieux_MISCELLANEOUS, acute or chronic hepatitis C virus infection, business.industry, hepatitis C virus genotype 4, HCV, antibody response, virus diseases, Hepatitis C, medicine.disease, Virology, digestive system diseases, 3. Good health, 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, chemistry, Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, lcsh:Q, 030211 gastroenterology & hepatology, business, Biotechnology
Abstract: Hepatitis C is one of the leading causes of hepatocellular carcinoma and remains at a high prevalence in Egypt and other resource-limited countries. Several hepatitis C virus (HCV) genotypes are distributed throughout the world, with genotype 4 being most common in North and Central Africa. We developed a multiplex serological assay for the detection of the HCV specific humoral immune response, with a focus on genotype 4. For the multiplex HCV assay we used twelve antigenic regions of different HCV proteins (core, and non-structural (NS) proteins NS3, NS4, NS5A, NS5B) and validated the assay technically and clinically. In comparison to a commercially available test, our assay revealed a higher sensitivity for genotype 4, and is therefore more suited for studying immune seroconversion in samples from acutely infected Egyptian HCV patients. Furthermore, our assay discriminates acutely and chronically infected HCV patients. Of 296 well characterized HCV patient samples, 83.9% of the acute samples and 86.5% of the chronic samples could be correctly classified. In sum, this newly developed serological HCV assay has a higher sensitivity for HCV genotype 4, and can thus improve diagnostic accuracy. Through the discrimination of acutely and chronically infected HCV patients the assay may be useful in supporting clinical management of HCV patients.
Published: 2017

14. Development of a Bead-Based Multiplex Assay for the Analysis of the Serological Response against the Six Pathogens HAV, HBV, HCV, CMV, T. gondii, and H. pylori

Author: Angela Filomena, Darragh Duffy, Manas K. Akmatov, Gérard Krause, Thomas O. Joos, Barbara Gärtner, Frank Pessler, Matthew L. Albert, Nicole Schneiderhan-Marra, Markus Gerhard, Natural and Medical Sciences Institute [Reutlingen] (NMI), Centre for Experimental and Clinical Infection Research [Hanover] (TWINCORE), Helmholtz Centre for Infection Research (HZI), Centre for Individualized Infection Medicine [Hanover], Translational Infrastructure Epidemiology [Hanover], German Centre for Infection Research (DZIF), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris], Institut für Mikrobiologie und Hygiene [Homburg/Saar], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Part of this work was supported by the European Commission FP7 project SPHINX (grant reference no. 261365). We thank Hannelore Meyer and Luca Formichella, Technical University of Munich, for sending the samples for the H. pylori assay., European Project: 261365,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,SPHINX(2010), Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr.7, 38124 Braunschweig, Germany., Vougny, Marie-Christine, Spontaneous clearance in Patients acutely infected with HCV - Immune profiling, Novel biomarkers and X-omics approaches - SPHINX - - EC:FP7:HEALTH2010-11-01 - 2014-04-30 - 261365 - VALID, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP), and Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
Subjects: 0301 basic medicine, [SDV.IMM] Life Sciences [q-bio]/Immunology, Hepatitis C virus, Population, Biomedical Engineering, Toxoplasma gondii, Bioengineering, medicine.disease_cause, Biochemistry, Virus, Article, lcsh:Chemistry, 03 medical and health sciences, 0302 clinical medicine, medicine, Seroprevalence, Multiplex, hepatitis, 030212 general & internal medicine, education, lcsh:Science, lcsh:QH301-705.5, Hepatitis, Hepatitis B virus, education.field_of_study, serotest, seroprevalence, Helicobacter pylori, business.industry, Hepatitis A, medicine.disease, Virology, 3. Good health, multiplex, 030104 developmental biology, multi-pathogen assay, lcsh:Biology (General), lcsh:QD1-999, cytomegalovirus (CMV), [SDV.IMM]Life Sciences [q-bio]/Immunology, lcsh:Q, business, Biotechnology
Abstract: International audience; The spread of infectious diseases and vaccination history are common subjects of epidemiological and immunological research studies. Multiplexed serological assays are useful tools for assessing both current and previous infections as well as vaccination efficacy. We developed a serological multi-pathogen assay for hepatitis A, B and C virus, cytomegalovirus (CMV), Toxoplasma gondii, and Helicobacter pylori using a bead-based multiplex assay format. The multi-pathogen assay consisting of 15 antigens was utilized for the analysis of the serological response in elderly individuals of an influenza vaccination study (n = 34). The technical assay validation revealed a mean intra-assay precision of coefficient of variation (CV) = 3.2 ± 1.5% and a mean inter-assay precision of CV = 8.2 ± 5.3% across all 15 antigens and all tested samples, indicating a robust test system. Furthermore, the assay shows high sensitivities (ranging between 94% and 100%) and specificities (ranging between 93% and 100%) for the different pathogens. The highest seroprevalence rates in our cohort were observed for hepatitis A virus (HAV; 73.5%), followed by CMV (70.6%), T. gondii (67.6%) and H. pylori (32.4%). Seroprevalences for hepatitis B virus (HBV, 8.8%) and hepatitis C virus (HCV, 0%) were low. The seroprevalences observed in our study were similar to those from other population-based studies in Germany. In summary, we conclude that our multiplex serological assay represents a suitable tool for epidemiological studies.
Published: 2017

15. CXCR3/CXCL10 Axis Shapes Tissue Distribution of Memory Phenotype CD8 + T Cells in Nonimmunized Mice

Author: Molly A. Ingersoll, Matthew L. Albert, Philippe Bousso, David Michonneau, Cécile Alanio, Rosa Barreira da Silva, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Department of Cancer Immunology, Genentech, Inc. [San Francisco], Dynamiques des Réponses immunes - Dynamics of Immune Responses, This work was supported by the Agence National de la Recherche (ANR-14-CE14-0030 PriCelAge to C.A. and M.L.A.), the Ligue contre le Cancer (to M.L.A.), the Fondation ARC pour la Recherche sur le Cancer (to M.L.A.), the European Union Seventh Framework Programme Marie Curie Action (PCIG11-GA-2012-3221170 to M.A.I.), and the French Government’s Invest in the Future Program, managed by the Agence Nationale de la Recherche (LabEx Immuno-Onco [to C.A., R.B.d.S., M.A.I., and M.L.A.] and LabEx Milieu Interieur [postdoctoral fellowship to C.A. and M.L.A.]). C.A. received a Ph.D. fellowship from Institut National du Cancer (Soutien à la Recherche Formation en Recherche Translationelle), and R.B.d.S. was the recipient of a Pasteur-Roux postdoctoral fellowship from the Institut Pasteur., ANR-14-CE14-0030,PriCelAge,Induction de réponses cellulaires T avec l'âge avancé(2014), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]
Subjects: 0301 basic medicine, education.field_of_study, Transgene, Immunology, Population, T-cell receptor, hemic and immune systems, Biology, CXCR3, Phenotype, Cell biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Immunology and Allergy, CXCL10, Cytotoxic T cell, [SDV.IMM]Life Sciences [q-bio]/Immunology, education, CD8, 030215 immunology
Abstract: The preimmune repertoire consists of mature T lymphocytes that have not yet been stimulated in the periphery. Memory phenotype (MP) cells have been reported as part of the preimmune repertoire (i.e., T cells bearing memory markers despite lack of engagement with cognate Ag); however, little is known about their trafficking and function. In this study, we hypothesized that MP cells, naive to TCR stimulation, constitute a transient population that traffics to tissues during development. Using mutant and transgenic animals with a monospecific TCR, we discovered increased numbers of MP CD8+ T cells circulating in nonimmunized Cxcr3−/− and Cxcl10−/− mice compared with wild-type animals. Phenotypic differences included decreased numbers of preimmune MP Ag-specific T cells in the skin and thymus and a distinct pattern of activation upon TCR engagement. Our results show for the first time, to our knowledge, an important role for CXCR3 and CXCL10 in the tissue distribution of preimmune MP cells.
Published: 2017

16. Deconvolution of the Response to Bacillus Calmette–Guérin Reveals NF-κB-Induced Cytokines As Autocrine Mediators of Innate Immunity

Author: Aurélie Bisiaux, Jeremy Boussier, Darragh Duffy, Lluis Quintana-Murci, Magnus Fontes, Matthew L. Albert, The Milieu Intérieur Consortium, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), International Group for Data Analysis (IGDA), Institut Pasteur [Paris], Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Genentech, Inc. [San Francisco], This work benefited from support of the French government’s 'Invest in the Future program,' managed by the Agence Nationale de la Recherche (ANR, reference 10-LABX-69-01 and LabEx Immuno-Onco) and from The Ligue Contre le Cancer and the French National Institute for Cancer Research (INCA)., The authors would like to thank Dr. Molly Ingersoll for helpful discussion and critical reading of the manuscript. We also thank the members of the Milieu Intérieur consortium for their advice and input on the project., ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Vougny, Marie-Christine, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: lcsh:Immunologic diseases. Allergy, 0301 basic medicine, Cell type, immune monitoring, [SDV.IMM] Life Sciences [q-bio]/Immunology, mycobacteria, Lymphocyte, medicine.medical_treatment, Immunology, Jak-1/2 inhibitors, Biology, 03 medical and health sciences, chemistry.chemical_compound, medicine, Immunology and Allergy, Receptor, Autocrine signalling, Original Research, Innate immune system, NF-κB, Immunotherapy, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Cytokine, chemistry, toll-like receptors, Dectin-1/2, [SDV.IMM]Life Sciences [q-bio]/Immunology, lcsh:RC581-607
Abstract: International audience; Bacillus Calmette-Guérin (BCG) is used as a vaccine and diagnostic test for tuberculosis, as well as immunotherapy in the treatment of bladder cancer. While clinically useful, the response to mycobacterial stimulation is complex and the induced protein signature remains poorly defined. We characterized the cell types directly engaged by BCG, as well as the induced cytokine loops that transmit signal(s) to bystander cells. Standardized whole-blood stimulations and mechanistic studies on single and purified cell populations identified distinct patterns of activation in monocytes as compared to neutrophils and invariant lymphocyte populations. Deconvoluting the role of Toll-like receptor 2/4 and Dectin-1/2 in the inflammatory response to BCG, we revealed Dectin-1/2 as dominant in neutrophils as compared to monocytes, which equally engaged both pathways. Furthermore, we quantified the role of NF-κB and NADPH/reactive oxygen species (ROS)-dependent cytokines, which triggered a JAK1/2-dependent amplification loop and accounted for 40-50% of the induced response to BCG. In sum, this study provides new insight into the molecular and cellular pathways involved in the response to BCG, establishing the basis for a new generation of immunodiagnostic tools.
Published: 2017

17. Inhibition of polyamine biosynthesis is a broad-spectrum strategy against RNA viruses

Author: Matthew L. Albert, Marie-Pascale Frenkiel, Anavaj Sakuntabhai, Carole Tamietti, Anna Yakovleva, Marco Vignuzzi, Francis Delpeyroux, Bryan C. Mounce, Sandrine Vitry, Scott W. Werneke, Etienne Simon-Loriere, Cécile Khou, Everett Clinton Smith, Mark R. Denison, Nathalie Pardigon, Marie Flamand, Peter Jan Hooikaas, Enzo Z. Poirier, Teresa Cesaro, Gonzalo Moratorio, Matthieu Prot, Monique Lafon, Romain Volle, Giovanna Barba-Spaeth, Populations virales et Pathogenèse - Viral Populations and Pathogenesis, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Virologie Structurale - Structural Virology, Neuro-Immunologie Virale - Viral Neuro-immunology, Biologie des virus entériques (BVE), Environnement et Risques infectieux - Environment and Infectious Risks (ERI), Institut Pasteur [Paris] (IP), This work was funded by the Laboratoire d’Excellence via Integrative Biology of Emerging Infectious Diseases (grant no. ANR-10-LABX-62-IBEID to B.C.M. and M.V.), Equipe FRM DEQ20150331759 from the French Fondation pour la Recherche Médicale (to M.V.), Institut Pasteur Defeat Dengue Program (to B.C.M. and M.V.), Erasmus Unipharma-Graduates Program (to T.C.), Amgen Scholars Program at Institut Pasteur (to A.Y.), Het Weerstandfonds (to P.J.H), NIH (grant no.R01AI108197 to M.R.D.), NIH (grant no. U19 AI109680 to M.R.D.), InstitutPasteur Programme Transversal de Recherche (grant no. ZPTR484 to F.D.), Fondation Total (grant no. S-CM15010-05B to F.D.), Roux Howard Cantarini postdoctoral fellowship (to R.V.), Seventh Framework Programme (grant no. 278433-PREDEMICS to N.P.), and Ministry of Defense, Direction Générale de l’Armement (to C.K.)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 278433,EC:FP7:HEALTH,FP7-HEALTH-2011-two-stage,PREDEMICS(2011), Vougny, Marie-Christine, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Preparedness, Prediction and Prevention of Emerging Zoonotic Viruses with Pandemic Potential using Multidisciplinary Approaches - PREDEMICS - - EC:FP7:HEALTH2011-11-01 - 2016-10-31 - 278433 - VALID, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris]
Subjects: 0301 basic medicine, MESH: Hemorrhagic Fever, Ebola/virology, viruses, Spermine, medicine.disease_cause, Virus Replication, Disease Outbreaks, chemistry.chemical_compound, Mice, Polyamines, Diethylnorspermine, MESH: Animals, MESH: Disease Outbreaks, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, education.field_of_study, Zika Virus Infection, MESH: Chikungunya virus/metabolism, MESH: Antiviral Agents/pharmacology, MESH: Spermine/pharmacology, Ebolavirus, MESH: Virus Replication/drug effects, 3. Good health, MESH: Chikungunya Fever/virology, MESH: Polyamines/metabolism, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Ebolavirus/drug effects, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Zika Virus Infection/virology, Chikungunya virus, Eflornithine, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Population, MESH: Hemorrhagic Fever, Ebola/drug therapy, MESH: Chikungunya virus/drug effects, Biology, Microbiology, Antiviral Agents, Virus, Cell Line, 03 medical and health sciences, MESH: Acetyltransferases/metabolism, Acetyltransferases, MESH: Mice, Inbred C57BL, Virology, Vaccines and Antiviral Agents, medicine, Animals, Humans, RNA Viruses, MESH: Zika Virus/drug effects, education, MESH: Mice, MESH: Spermine/analogs & derivatives, Ebola virus, MESH: Humans, RNA, Zika Virus, Hemorrhagic Fever, Ebola, MESH: Zika Virus Infection/drug therapy, MESH: Cell Line, Mice, Inbred C57BL, MESH: Eflornithine/pharmacology, 030104 developmental biology, MESH: RNA Viruses/drug effects, chemistry, Viral replication, Insect Science, Chikungunya Fever, MESH: Chikungunya Fever/drug therapy, Polyamine, MESH: Ebolavirus/metabolism
Abstract: RNA viruses present an extraordinary threat to human health, given their sudden and unpredictable appearance, the potential for rapid spread among the human population, and their ability to evolve resistance to antiviral therapies. The recent emergence of chikungunya virus, Zika virus, and Ebola virus highlights the struggles to contain outbreaks. A significant hurdle is the availability of antivirals to treat the infected or protect at-risk populations. While several compounds show promise in vitro and in vivo , these outbreaks underscore the need to accelerate drug discovery. The replication of several viruses has been described to rely on host polyamines, small and abundant positively charged molecules found in the cell. Here, we describe the antiviral effects of two molecules that alter polyamine levels: difluoromethylornithine (DFMO; also called eflornithine), which is a suicide inhibitor of ornithine decarboxylase 1 (ODC1), and diethylnorspermine (DENSpm), an activator of spermidine/spermine N 1 -acetyltransferase (SAT1). We show that reducing polyamine levels has a negative effect on diverse RNA viruses, including several viruses involved in recent outbreaks, in vitro and in vivo . These findings highlight the importance of the polyamine biosynthetic pathway to viral replication, as well as its potential as a target in the development of further antivirals or currently available molecules, such as DFMO. IMPORTANCE RNA viruses present a significant hazard to human health, and combatting these viruses requires the exploration of new avenues for targeting viral replication. Polyamines, small positively charged molecules within the cell, have been demonstrated to facilitate infection for a few different viruses. Our study demonstrates that diverse RNA viruses rely on the polyamine pathway for replication and highlights polyamine biosynthesis as a promising drug target.
Published: 2016

18. Bladder catheterization increases susceptibility to infection that can be prevented by prophylactic antibiotic treatment

Author: Kimberly A. Kline, H.M. Sharon Goh, Matthew L. Albert, Molly A. Ingersoll, Sarah Holec, Matthieu Rousseau, Rohan B. H. Williams, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), School of Biological Sciences, Singapore Centre for Environmental Life Sciences Engineering, National University of Singapore (NUS), This work benefitted from data assembled by the ImmGen Consortium (20). The authors wish to acknowledge the following funding: HMSG, SH, RBHW, and KAK were supported by the National Research Foundation (NRF) and Ministry of Education Singapore under its Research Centre of Excellence Programme. HMSG, SH, and KAK were supported by the NRF under its Singa-pore NRF Fellowship program (NRF-NRFF2011-11) and by the Ministry of Education Singapore under its Tier 2 program (MOE2014-T2-1-129). MAI was supported by funding from the European Union Seventh Framework Programme Marie Curie Action (PCIG11-GA-2012-3221170). Finally, this project was realized through the Merlion Programme, sponsored by the French Ministry of Foreign Affairs and Nanyang Technological University, to KAK and MAI., European Project: 3221170,European Union Seventh Framework Programme Marie Curie Action, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Vougny, Marie-Christine, and 3221170 - European Union Seventh Framework Programme Marie Curie Action - 3221170 - INCOMING
Subjects: 0301 basic medicine, medicine.medical_specialty, medicine.drug_class, Urinary system, medicine.medical_treatment, 030106 microbiology, Antibiotics, Urinary Bladder, Infections, Enterococcus faecalis, Urinary catheterization, Catheterization, 03 medical and health sciences, Internal medicine, medicine, Animals, Uropathogenic Escherichia coli, Urothelium, Antibiotic prophylaxis, Escherichia coli Infections, Gram-Positive Bacterial Infections, Inflammation, Urinary bladder, biology, business.industry, General Medicine, Antibiotic Prophylaxis, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, Surgery, Anti-Bacterial Agents, Mice, Inbred C57BL, Catheter, 030104 developmental biology, medicine.anatomical_structure, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Urinary Tract Infections, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Female, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, business, Urinary Catheterization, Research Article
Abstract: Catheter-associated urinary tract infections (CAUTI) are the most common hospital-associated infections. Here, we report that bladder catheterization initiated a persistent sterile inflammatory reaction within minutes of catheter implantation. Catheterization resulted in increased expression of genes associated with defense responses and cellular migration, with ensuing rapid and sustained innate immune cell infiltration into the bladder. Catheterization also resulted in hypersensitivity to Enterococcus faecalis and uropathogenic Escherichia coli (UPEC) infection, in which colonization was achieved using an inoculum 100-fold lower than the ID90 for infection of an undamaged urothelium with the same uropathogens. As the time of catheterization increased, however, colonization by the Gram-positive uropathogen E. faecalis was reduced, whereas catheterization created a sustained window of vulnerability to infection for Gram-negative UPEC over time. As CAUTI contributes to poorer patient outcomes and increased health care expenditures, we tested whether a single prophylactic antibiotic treatment, concurrent with catheterization, would prevent infection. We observed that antibiotic treatment protected against UPEC and E. faecalis bladder and catheter colonization as late as 6 hours after implantation. Thus, our study has revealed a simple, safe, and immediately employable intervention, with the potential to decrease one of the most costly hospital-incurred infections, thereby improving patient and health care economic outcome. NRF (Natl Research Foundation, S’pore) MOE (Min. of Education, S’pore) Published version
Published: 2016

19. Inhibition of DPP4 activity in humans establishes its in vivo role in CXCL10 post‐translational modification: prospective placebo‐controlled clinical studies

Author: Stanislas Pol, Grace Linder, Kristin V. Tarbell, Jérémie Decalf, Vincent Mallet, Matthew L. Albert, Armanda Casrouge, Estelle Mottez, Darragh Duffy, Jeffrey D. Price, Philippe Sultanik, Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris] - Institut National de la Santé et de la Recherche Médicale (INSERM), Diabetes Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Centre d'Immunologie Humaine (CIH), Service d'hépatologie médicale [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Cochin [AP-HP], Institut Pasteur [Paris], Department of Cancer Immunology, Genentech, Inc. [San Francisco], This work was supported by the Agence nationale de recherches sur le sida et les hépatites virales (ANRS) and the Ligue nationale contre le cancer and by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), National Institutes of Health [Bethesda] (NIH), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Vougny, Marie-Christine
Subjects: 0301 basic medicine, Chemokine, [SDV.IMM] Life Sciences [q-bio]/Immunology, Dipeptidyl Peptidase 4, [SDV]Life Sciences [q-bio], Lymphocyte, chemokines, Pharmacology, Biology, DPP4, Placebos, 03 medical and health sciences, 0302 clinical medicine, In vivo, Report, medicine, Humans, CXCL10, Prospective Studies, Pharmacology & Drug Discovery, post‐translational modifications, Dipeptidyl peptidase-4, Dipeptidyl-Peptidase IV Inhibitors, Sitagliptin Phosphate, Antagonist, Post-translational Modifications, Proteolysis & Proteomics, Hepatitis C, Chronic, clinical study, Healthy Volunteers, Microbiology, Virology & Host Pathogen Interaction, 3. Good health, Chemokine CXCL10, Clinical trial, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Sitagliptin, Proteolysis, Immunology, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Molecular Medicine, Protein Processing, Post-Translational, Reports, medicine.drug
Abstract: International audience; Biochemical experiments, animal models, and observational studies in humans all support a role of dipeptidyl peptidase 4 (DPP4) in the N-terminal truncation of CXCL10, which results in the generation of an antagonist form of the chemokine that limits T-cell and NK cell migration. Motivated by the ability to regulate lymphocyte trafficking in vivo, we conducted two prospective clinical trials to test the effects of DPP4 inhibition on CXCL10 processing in healthy donors and in chronic hepatitis C patients, a disease in which DPP4 levels are found to be elevated. Participants were treated daily with 100 mg sitagliptin, a clinically approved DPP4 inhibitor. Plasma samples were analyzed using an ultrasensitive single-molecule assay (Simoa) to distinguish the full-length CXCL101-77 from the NH2-truncated CXCL103-77, as compared to the total CXCL10 levels. Sitagliptin treatment resulted in a significant decrease in CXCL103-77 concentration, a reciprocal increase in CXCL101-77, with only minimal effects on total levels of the chemokine. These data provide the first direct evidence that in vivo DPP4 inhibition in humans can preserve the bioactive form of CXCL10, offering new therapeutic opportunities for DPP4 inhibitors.
Published: 2016

20. Sumoylation coordinates the repression of inflammatory and anti-viral gene-expression programs during innate sensing

Author: Aymeric Silvin, Pierre-Emmanuel Joubert, Jacob-Sebastian Seeler, Ido Amit, Joao G. Magalhaes, Nicolas Manel, Jack-Christophe Cossec, Anne Dejean, Adrien Decque, Olivier Joffre, Ronnie Blecher-Gonen, Sebastian Amigorena, Pierre Lapaquette, Matthew L. Albert, Organisation Nucléaire et Oncogenèse / Nuclear Organization and Oncogenesis, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Weizmann Institute of Science [Rehovot, Israël], Immunobiologie des Cellules Dendritiques, Supported by Institut National du Cancer (PLBIO13-057 to S.A.), Agence Nationale de la Recherche (ANR-14-CE16 to S.A.), Ligue Nationale Contre le Cancer (Equipes labellisées, A. Dejean and S.A.), Fondation pour la Recherche Médicale (FRM, AJE201212 to O.J.), Région-Midi-Pyrénées (NVEQ 2014 to O.J.), European Research Council ('SUMOSTRESS' to A. Dejean, 'DC-BIOX340046' to S.A., and 'HIVINNATE' (309848) to N.M.), Ecole Normale Supérieure (A. Decque) and Odyssey-RE (A. Decque)., We thank M. Dasso (US National Institutes of Health) for antibody to SUMO-2, A. Garcia-Sastre(Icahn School of Medicine at Mount Sinai) for antibody to HA, A. Andrieux and J.-M. Carpier for technical help, Philippe Sansonetti (Pasteur Institute, Paris) for S. flexneri, and M. Yaniv for critical reading of the manuscript. Sequencing was performed by the Institut Génétique Biologie Moléculaire Cellulaire Microarray and Sequencing platform, a member of the 'France Génomique' consortium (ANR-10-INBS-0009)., ANR-14-CE16-0014,IS-Therapeutics,Caractérisation des cibles du domaine immunosuppresseur des envelopes rétrovirales: récepteur et voies de signalisation/ nouvelles approches thérapeutiques(2014), European Project: 294341,EC:FP7:ERC,ERC-2011-ADG_20110310,SUMOSTRESS(2013), European Project: 309848,EC:FP7:ERC,ERC-2012-StG_20111109,HIVINNATE(2013), European Project: 340046,EC:FP7:ERC,ERC-2013-ADG,DCBIOX(2014), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Organisation Nucléaire et Oncogenèse, Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), and Weizmann Institute of Science
Subjects: Lipopolysaccharides, 0301 basic medicine, MESH: Chromatin/genetics, MESH: Signal Transduction, MESH: Immunity, Innate, medicine.medical_treatment, SUMO protein, Receptor, Interferon alpha-beta, MESH: Inflammation/genetics, MESH: Mice, Knockout, Mice, Interferon, MESH: Shock, Septic/immunology, Immunology and Allergy, MESH: Animals, Regulatory Elements, Transcriptional, Disease Resistance, MESH: Dendritic Cells/metabolism, Mice, Knockout, Toll-Like Receptors, MESH: Gene Expression Regulation, Pattern recognition receptor, MESH: Inflammation/metabolism, Shock, Septic, Chromatin, Cell biology, Enhancer Elements, Genetic, Cytokine, MESH: Dendritic Cells/immunology, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Disease Susceptibility, Inflammation Mediators, medicine.symptom, Signal transduction, MESH: SUMO-1 Protein/metabolism, MESH: Inflammation Mediators/metabolism, Protein Binding, Signal Transduction, medicine.drug, Pattern recognition receptors, MESH: Sumoylation*/genetics, MESH: Toll-Like Receptors/metabolism, MESH: Inflammation/virology, SUMO-1 Protein, Immunology, MESH: Chromatin/metabolism, MESH: Sumoylation*/immunology, MESH: Disease Susceptibility, Inflammation, Biology, MESH: Immunomodulation, MESH: Genetic Loci, MESH: Lipopolysaccharides/immunology, Proinflammatory cytokine, Immunomodulation, 03 medical and health sciences, MESH: Gene Expression Profiling, MESH: Regulatory Elements, Transcriptional, medicine, Animals, Gene silencing, MESH: Protein Binding, MESH: Receptor, Interferon alpha-beta/metabolism, MESH: Mice, Gene Expression Profiling, MESH: Shock, Septic/genetics, Sumoylation, Dendritic Cells, Interferon-beta, MESH: Interferon-beta/metabolism, MESH: Shock, Septic/metabolism, Immunity, Innate, Disease Models, Animal, Gene regulation in immune cells, MESH: Inflammation/immunology, 030104 developmental biology, MESH: Disease Resistance, Gene Expression Regulation, Genetic Loci, MESH: Enhancer Elements, Genetic, MESH: Cytokines/metabolism, MESH: Disease Models, Animal
Abstract: International audience; Innate sensing of pathogens initiates inflammatory cytokine responses that need to be tightly controlled. We found here that after engagement of Toll-like receptors (TLRs) in myeloid cells, deficient sumoylation caused increased secretion of transcription factor NF-κB-dependent inflammatory cytokines and a massive type I interferon signature. In mice, diminished sumoylation conferred susceptibility to endotoxin shock and resistance to viral infection. Overproduction of several NF-κB-dependent inflammatory cytokines required expression of the type I interferon receptor, which identified type I interferon as a central sumoylation-controlled hub for inflammation. Mechanistically, the small ubiquitin-like modifier SUMO operated from a distal enhancer of the gene encoding interferon-β (Ifnb1) to silence both basal and stimulus-induced activity of the Ifnb1 promoter. Therefore, sumoylation restrained inflammation by silencing Ifnb1 expression and by strictly suppressing an unanticipated priming by type I interferons of the TLR-induced production of inflammatory cytokines
Published: 2016

21. Erratum

Author: Sascha Martens, Masashi Narita, Rajkumar Cheluvappa, Kevin A. Roth, Ta Yuan Chang, Kartik Venkatachalam, Chang-Shen Lin, Sharon G. Adler, Flaminia Pavone, Dianwen Ju, Michelle A. Ozbun, Michael R. Duchen, Shu Feng Zhou, Wei-Guo Zhu, Aaron Di Antonio, Defeng Wu, Taixing Cui, Xu Guang Guo, Zhiping Xie, Lorena García Nannig, Eloy Bejarano, Stéphane D. Lemaire, Petro Starokadomskyy, Hyung Ryong Kim, Mario Pinar, Rebecca T. Marquez, Zvenyslava Husak, Anthony R. White, Joanna Poulton, Antonis S. Zervos, Shweta Sharma, Jochen Walter, Nicholas T. Ktistakis, Christopher H.K. Cheng, Sunhee Lee, Yuen Li Chung, Howard O. Fearnhead, Young J. Oh, Ivano Amelio, Guillermo A. Blanco, Jan Simak, Junfang Wu, Yingying Lu, Mary Kate McBrayer, Soo Han Bae, Ichizo Nishino, Hong-Ming Hu, Benjamin R. Underwood, Tomonori Kimura, Zexian Liu, Savithrama P. Dinesh-Kumar, Qian Yang, Andreas Kern, Hsing Jien Kung, Jan B. Parys, Cam Patterson, Celine Perier, Toshiro Okazaki, Daisuke Koya, Avinash Sonawane, Cédric Cleyrat, Robert I. Richards, Kai Y. Soo, Rodrigo Mora-Rodriguez, Gigi N.C. Chiu, Moon Moo Kim, Vladimir N. Uversky, Shengfang Ge, Matthew T. V. Chan, Irene Kyrmizi, Lara Gibellini, Ángela M. Valverde, Erik Norberg, Fan Zhang, Jan C. Koch, Alec C. Kimmelman, Jingfang Ju, Jie Bai, Lei Duan, Paulina Ordonez, Shuwen Liu, Wolfdieter Springer, Eric Deutsch, Elena Ortona, Jose M. Seguí-Simarro, Vinay Choubey, Leonidas Stefanis, Robert G. Hawley, Claudia Bincoletto, Xian-Hui He, Zhifen Yang, Thomas M. Durcan, Martine Biard-Piechaczyk, Kui Lin, Hongming Pan, Konstantinos Kambas, Cristina Muñoz-Pinedo, Marta Magariños, Yoshinori Takahashi, Adrienne M. Gorman, Philippe Gailly, Takahiko Akematsu, Justine D. Mintern, Liang Xu, Tetsuo Shioi, Luis M. Botana, Yule Liu, Yong Yeon Cho, Jinzhi Lei, Eung Kweon Kim, Alakananda Basu, Vikash Kumar Dubey, Candelaria Gomez-Manzano, Avital Eisenberg-Lerner, Chuan-Ming Xie, Wenjie Dai, Pedro Gonzalez-Alegre, Maria Condello, Zheng-Hong Qin, Zhi-Min Yuan, Catherine Andreadi, Anna Rita Migliaccio, Chong Liu, Michaël Boyer-Guittaut, Melanie Denizot, Esperanza Arias, Greet Van den Berghe, Guomei Tang, Timothy P. Devarenne, Xianyong Sheng, Louis R. Lapierre, J. Wade Harper, Zuzana Storchova, Aileen R. Ariosa, Sug Hyung Lee, Qi Zeng, Godefridus J. Peters, Daniela L. Papademetrio, Alexandre Arcaro, Zhiyuan Yao, Pablo Iribarren, Mario Chiariello, Maria Rosaria Torrisi, Parimal Karmakar, Yong Huang, Sebastiano Sciarretta, Nathalie Andrieu-Abadie, László Fésüs, Patricia Boya, Ruediger Rudolf, Leonor Miller-Fleming, Vasilis J. Promponas, Juan Segura-Aguilar, Paula Daza, Shiow Ju Lee, Songshu Meng, Paul K. Herman, Ludwig Eichinger, Ye-Guang Chen, Kay F. Macleod, Thomas Simmet, Cristina Corral-Ramos, Claudio Brancolini, Jun Ren, Ying Jiang, Benoît Derrien, Xiao Fang Yu, Qing Zhong, Zong Wan Mao, Xingcong Ren, Armando A. Genazzani, Marina Pierdominici, Sanbing Shen, Sandra Moreno, Hana Algül, Maurizio Renna, Ricardo Sánchez-Prieto, Ashok K. Saluja, Yasuo Uchiyama, Pope L. Moseley, Victor E. Dosenko, Chun-Feng Liu, Bakhos A. Tannous, Efthimios Sivridis, Baharia Mograbi, Michiko Shintani, Amanda S. Bess, Rodrigo Portes Ureshino, Avnika A. Ruparelia, Paul Hofman, Eric Chevet, Martha M. Monick, Hong Gang Wang, Daping Fan, Jorge Moscat, Giuseppe Matarese, Consiglia Pacelli, Young Seok Cho, Miriam Cnop, Stefan Böckler, Nikolai V. Gorbunov, Christina J. Sigurdson, Hang T.T. Nguyen, Aurélie François, Katarina Kågedal, Sam Gandy, Silvia Campello, Alain Bruhat, Filomena Fiorito, Hua Feng, Man Tian Mi, Gian Maria Fimia, Masaki Tanaka, Guofei Zhou, José L. Crespo, Heinz Jungbluth, Anna Chiara Nascimbeni, Arianne L. Theiss, Svetlana Dokudovskaya, Mar Lorente, Sergio Lavandero, Yu Xia Zhao, Fangming Lin, Yuchen Feng, Gad Galili, Silvia Cetrullo, Paula I. Moreira, Dhyan Chandra, Dimitrios J. Stravopodis, Roberta A. Gottlieb, Gregory A. Taylor, Longping Wen, Faqiang Li, Marco Sardiello, Umesh K. Jinwal, Francesca Belleudi, Lan Tan, Livia Di Renzo, Tamas Korcsmaros, Xinbing Sui, Douglas R. Green, Guillermo Mazzolini, Hervé Le Stunff, Kelly S. Doran, Mary E. Choi, Carlos S. Subauste, Natalia Rodriguez-Muela, Nicholas J. Talbot, Marta Palmieri, Sonia Hernández-Tiedra, Ligia C. Gomes, Irving M. Shapiro, Makoto Ubukata, Mario P. Tschan, Baris Bingol, Benjamin Loos, Terry Kwok, Luca M. Neri, Sreejayan Nair, Michele Wolfe Bianchi, Ralf Erdmann, Alexander Greenhough, Neeraj Vij, Jeong Hun Kim, Satoaki Matoba, Bo Liu, George R. Beck, Michael Moore, Vrajesh V. Parekh, Kyle A. Bauckman, Li-Lin Du, Mikihiro Fujiya, Yan G. Zhao, Renaud Legouis, Jiangwei Zhang, Kailiang Jia, Nadezda Apostolova, Sehamuddin Galadari, Khosrow Adeli, Ming Yong Zhang, Carmela Fusco, Angel Ortega, Anna Pensalfini, Zsuzsanna Szatmári, Marco Tafani, Isabella Ceccherini, Anne Hamacher-Brady, Kuen Jer Tsai, Anita C. Truttmann, Franco Fortunato, Keisuke Miyazawa, Chunhai Fan, Berge A. Minassian, Jian Zhang, Frank A. Anania, Heesun Cheong, Amal O. Amer, Ing Swie Goping, Won-Ki Huh, Anita Solhaug, Joan Cl ria, Laurent Le Cam, Seungmin Hwang, Karen L. Wright, Antonella De Matteis, Troy T. Rohn, Ivana Bjedov, Subbiah Pugazhenthi, Hal E. Broxmeyer, Xue Yuan Bai, Koenraad Norga, Minnie M. Sarwal, Daniel F. Schorderet, Ioannis P. Nezis, Mei Qing Wang, Jun Hee Lee, Yong J. Lee, David A. Tumbarello, Fernando Macian, Joern Dengjel, Dmitry V. Bulavin, Andrew J. Halayko, Ben Berkhout, Aseem Pandey, Santosh Kesari, Karin Przyklenk, Elena V. Tchetina, Matthew L. Albert, Laura Segatori, Joel N. Meyer, Mustapha Rouis, Éva Margittai, Ashish Jain, David Hahn, Thomas Vaccari, Lori R. Covey, Ghanshyam Swarup, Kuo Yang Huang, Gennaro Napolitano, Sam W. Lee, Seong Who Kim, Alberto Anel, Vladimir V. Rogov, Laura A. Carleton, Amine Belaid, Byoung Kuk Jang, Sheng-Han Kuo, Patricia L. Yeyati, Jae U. Jung, Teresa Zoladek, Sabrina Di Bartolomeo, Clémence Richetta, Peixin Yang, Daniela Trisciuoglio, Hye Seung Jung, Katsumi Higaki, Eui-Bae Jeung, Ivan Topisirovic, Isabella Caniggia, Susan E. Logue, Issidora S. Papassideri, Lynda A. Morrison, Caihong Wang, Graeme Sargent, Beth Levine, Mingxiang Ye, David M. Sabatini, Consuelo Amantini, Julio A. Aguirre-Ghiso, Lawrence H. Boise, Patricia Silvia Romano, Sean T. Sweeney, Takayuki Tsukuba, Reinhard Dechant, Benoit Barbeau, Marta Martinez-Vicente, Kuo How Huang, Edésio José Tenório de Melo, Faustino Mollinedo, José M. Fuentes, Joaquín Jordán, Dong-Hyung Cho, Dexian Zheng, Jeroen J.M. Hoozemans, Zhong Chen, Waleska Kerllen Martins, Abraham Acevedo Arozena, Marcos P. Thomé, Gordon C. Shore, Fabienne C. Fiesel, Teng Jiang, Feng Han, Marc Poirot, Anne Sophie Nicot, Eileen White, Olivier Feron, Arthur I. Cederbaum, Wen Bin Qian, Yingjie Sun, Rejko Krüger, Shingo Kajimura, Jianzhen Xu, Shang Der Chen, Maximiliano G. Gutierrez, Zhengping Yu, Jiaren Sun, Utpal Sen, Giovanna Galliciotti, Hilde Nilsen, Benjamin T. Kopp, Benedikt Westermann, Inmaculada Galindo, Eeva-Liisa Eskelinen, Rubem F. S. Menna-Barreto, Guillermo Mariño, Andrea Ballabio, Izabela Poprawa, Yanjin Zhang, Clay F. Semenkovich, Martin E. Fernandez-Zapico, Helin Vakifahmetoglu-Norberg, Hongchi Jiang, Eugenia Morselli, Angelo A. Manfredi, Marianne Boes, Han-Jung Chae, Covadonga Alonso, Min Chen, Safia Costes, David Kessel, Rakesh Kumar, Yang Zhang, Reinhild Prange, Vassiliki E. Mpakou, Laura Santambrogio, Javier E. Irazoqui, Anna Skwarska, Junichi Sadoshima, Rika Umemiya-Shirafuji, Michael I. Koukourakis, Norma Maugeri, Yuqing Wang, Pedro R. Cutillas, Jiqin Lian, Jiri Stulik, Takashi Ueno, Craig Montell, Rena Balzan, Meiyan Jin, Mara C. Duncan, Cathleen R. Carlin, Yasuo Yanagi, Maite G. Fernandez-Barrena, Yuyan Xiong, Martin Graef, Wei Yuan Yang, Renato V. Iozzo, Mark Screen, Patrick Brest, Haichao Wang, Ming Tan, Werner J. Kovacs, Weili Shen, Alessandro Fraldi, Paul Saftig, Alberto Faggioni, Krisna Prak, Christos E. Zois, Timothy E. Weaver, Marc Lecuit, Yu-Ying He, Michele Caraglia, Walter Balduini, M. Isabel G. Roncero, B. Schneider, Monika Cahova, Mathias Faure, Chihiro Sasakawa, Simon Michaeli, Sandy Giuliano, Dario C. Altieri, Eun-Kyeong Jo, Myung-Shik Lee, Carol Imbriano, John H. Brumell, Gustavo H. Goldman, Yan Wang, Junyan Shi, Quan Chen, Jayanta Debnath, Yonggeun Hong, Mohamed Amessou, Richard W. Wong, Robert E. Burke, Mauro De Santi, Trevor G. Shepherd, Anna Maria Joseph, Wouter G. van Doorn, Erkang Fei, Huey Lan Huang, F. Gisou van der Goot, Xinfeng Liu, Alexandru Almasan, Akiko Maeda, Yu Qiu, Yaohua Wu, Annie Sittler, Wen-Xing Ding, Wenhua Zhu, Hung-Jen Liu, Moisés Martínez-Velázquez, Jeffery S. Cox, Seung Yong Yoon, Concepcio Marin, Wilian A. Silveira, Fulvio Chiacchiera, W. Douglas Fairlie, Jian Xin Gao, Shuilong Leng, Nathan R. Brady, Josef M. Penninger, Puran Singh Sijwali, Florian Gruber, Tibor Vellai, Jiunn-Liang Ko, Laura Korhonen, Slimane Ait-Si-Ali, Hirokazu Arimoto, Alberto M. Martelli, Teresa L. M. Thurston, Chuanshan Xu, Kathrin Pallauf, Eduardo Couve, Shweta Saran, Lionel Blanc, Maylin Almonte-Beceril, Yong-Keun Jung, Lena Lavie, Junsoo Park, Camilla Palumbo, Claire H. Mitchell, Sophie Pattingre, Guillermo Velasco, Steve S.-L. Chen, Xiu-Fen Ming, Xin Qi, Vania Gelmetti, Nicolas Dupont, Soraya S. Smaili, Chinnaswamy Jagannath, Uta Dahmen, Daolin Tang, Rodrigo Franco, John H. Kehrl, Xiaonan Dong, Carsten Sachse, Jeff Kuret, Genzou Takemura, Supawadee Sukseree, Joëlle Botti, W. Haung Yu, Aurelia Lugea, Scott J. Bultman, Divaker Choubey, Frank A. Sinicrope, You-Wen He, Jian Wu, Yoshitaka Isaka, Geert Bultynck, Giuseppe Merla, Luigi Maiuri, Sonia Melino, Hannelore Maes, Daniele Lettieri Barbato, Ian G. Ganley, Zhihong Yang, Daniel Hofius, Kimberly McCall, Peiwen Chen, Istvan Lekli, Alicia Rosello, Eric Ghigo, Atsushi Kuno, Iman Tavassoly, Chris Albanese, Agustín Aranda, Salvatore Pepe, Hong Jiang, Henri Batoko, Giovanna Elvira Granato, Vincent Zecchini, Stephen E. Girardin, Maria T. Diaz-Meco, Philippe Marambaud, G. Amadoro, Sangeeta Khare, Christelle Koechlin-Ramonatxo, Emery H. Bresnick, Christian Behl, Mikio Nishimura, Julien Puyal, Wenjie Guo, Hsinyu Lee, Carolyn M. Sue, Derrick Gibbings, Alina Maloyan, Philippe Pierre, Serge N. Manié, Gerry Melino, Elizabeth A. Woodcock, Roberto Ciarcia, Liwen Jiang, Michael C. Kruer, Vladimir Trajkovic, Yunjiao Zhang, Nina Raben, Beata Pajak, Michael J. Ragusa, Riccardo Autelli, Kelly Jean Thomas, Suzana Gispert, Wei Li Zhao, Cheol Hyeon Kim, Pothana Saikumar, Arsenio Fernández-López, Juliano Machado, Valentina Iovane, Cai Ping Tan, Carmine Settembre, Neelam Azad, Yohta Shimada, Shivendra V. Singh, Hai Rao, Hirosato Mashima, Michael T. Stang, Yasuhito Sakuraba, Gemma Fabriàs, Tuck Wah Soong, Didac Carmona-Gutierrez, Ilse Vanhorebeek, F. Javier Oliver, Mondira Kundu, Alfonso Schiavi, Dan Lindholm, José L. Revuelta, Jason S. King, Susana Castro-Obregón, Paul Digard, Hua Zhu, Komal Raina, Yun Dai, Ruben K. Dagda, Nuria Martinez-Lopez, Andrea A. Gust, Lucia Notterpek, Robert Clarke, Manon E. Wildenberg, Mingzhou Chen, Leticia Reyes, Laura Berliocchi, John J. McMahon, Hongzhuan Chen, E.M. Nolte, Stefan W. Ryter, Fulvio Reggiori, Jiefei Geng, Michael A. Mandell, John H. Fingert, Holger Prokisch, Marina Jendrach, Søren R. Paludan, Elizabeth P. Henske, Ricardo Gargini, Wei-Xing Zong, Susmita Kaushik, Michael Overholtzer, Paul W. Sylvester, Daniel E. Voth, Canhua Huang, Andrea Boman, Gérard Lizard, Rut Valdor, Marc Flajolet, Graham S. Taylor, Nicola Di Daniele, Leonardo H. Travassos, Ying Yang, Anumantha G. Kanthasamy, Hasan Mukhtar, Yuhua Zhu, Noor Gammoh, Ignacio Vega-Naredo, Victoria Ryabovol, Sara W. Bird, Gang Min Hur, Qun-Ying Lei, Fan Yi, Laura Caberlotto, Maria F. Galindo, Bilal Piperdi, Leonidas C. Platanias, P. Hande Özdinler, Régis Delage-Mourroux, Julio Madrigal-Matute, Xu Liu, Nagio Takigawa, Aurora Pujol, Marta Margeta, Hee Jeong Kong, Christian Behrends, Michael Thumm, Shirley Luckhart, Emilio Clementi, John W. Steele, Liliana Schaefer, Philip L. Lorenzi, Chao-Yu Miao, She Min Lu, Jane E. Ishmael, Jin Hyoung Kim, V. Izzo, Yanming Wang, Balindiwe J.N. Sishi, Vincent Galy, Andras Perl, Shouqing Luo, Giovanni Vitale, Yongsheng Che, Rodrigo Troncoso, Liu Yang, Thomas J. Begley, Sebastien G. Bouret, Elizete Rizzo, James M. Piret, Junjun Wang, Herman P. Spaink, Thomas S. Jacques, Robin F. B. Turner, Young H. Lee, Eva Szegezdi, Daphne R. Goring, Manish K. Aghi, Rui Kang, Bart Staels, Midori Umekawa, Delia Goletti, Robert J. Bryson-Richardson, Ubaldo E. Martinez-Outschoorn, Luisa Dalla Valle, Giovanni Luca Gravina, Emad S. Alnemri, Maria Kaparakis-Liaskos, Konstantinos Ritis, Shalmoli Bhattacharyya, Alessandra Bolino, Xiaonan Zhao, Yoshihisa Watanabe, Christian Ungermann, Juan L. Iovanna, Katherine Williams, Ken Shirabe, Teresa S. Hawley, Sara Cherry, Ryuichiro Atarashi, Kozo Hamada, Seamus J. Martin, Shigeru Oshima, Mario Pende, Illana Gozes, Michel A. Duchosal, John J. Shacka, Shunhei Yamashina, Kithiganahalli Narayanaswamy Balaji, Richard L. Proia, Besim Ogretmen, Fang Hua, Koichi Araki, Charles Grose, Jia Luo, Helen K. W. Law, Charles Swanton, Liat Drucker, Guo Zhang, Zhizhuang J. Zhao, Anne K. Kenworthy, Javier A. Menendez, Gary Grant, Stig U. Andersen, Frank Lafont, Aparna Lakkaraju, Taijoon Chung, Leticia A.M. Carneiro, Monique Bernard, Gang Chen, Stephen W.G. Tait, Aimee L. Edinger, Jeffrey P. MacKeigan, Paul A. Ney, Mireia Niso-Santano, Valeria Crippa, Andreas S. Reichert, Isabelle Dugail, Jon D. Lane, Farida V. Minibayeva, Gianluca Tettamanti, Scott Pattison, Péter Lõrincz, Kamal Chowdhury, Ulrich E. Schaible, Maria Agnello, Paolo Pinton, Niels Jessen, Lei Guo, Kwang-Huei Lin, David N. Zacks, Ying Jan Wang, Simone Fulda, John J. Lemasters, Andrea Viale, Anna Maria Marconi, Valerie Askanas, Yoshitaka Nagai, François M. Vallette, Joan K. Heath, Srinivasan Dasarathy, Soo-Youl Kim, Günter U. Höglinger, Tamara Kravic-Stevovic, Iraide Alloza, Tiago F. Outeiro, Ana Serrano-Puebla, Elena A. Minina, Terrence M. Donohue, Ming Guo, Alexandra Giatromanolaki, Abdel Halim Harrath, Ken Sato, Anne Elisabeth Theron, Usha P. Andley, Claudio Cardinali, Maija Pesonen, Penny E. Lovat, Chanhee Kang, Sabah N. A. Hussain, Lisa A. Brennan, Jose A. Tapia, Christoph Becker, Huixin Yu, Pei-Yu Wang, Bertrand Joseph, Zhen Yan, Georgia Minakaki, Ricardo Escalante, Ralph A. Nixon, Katsuhiko Asanuma, M. Helena Vasconcelos, David J. Reiner, Shengkan Jin, David Dávila, Theo Rein, Balakrishna L. Lokeshwar, Antonio Miranda-Vizuete, Carl Ward, Vito Turk, Frederick D. Quinn, Katja Köhler, Masaru Harada, Kathleen Boesze-Battaglia, Fraser P. Coxon, Paulo R. Jannig, Miguel A. Peñalva, Manjula Kalia, Marco Corazzari, Chunjuan Song, Xianghua Yan, Lilach Toker, Benjamin Pineda, Vanessa Ginet, Ye Xu, Chun Jung Chen, Roberto Towns, Amy A. Kiger, Rajagopal Ramesh, Maria Rita Rippo, Joseph A. Hill, Boris Zhivotovsky, Peter Speck, Ya Hua, Peter J. Roach, Fabio Penna, Kasper M.A. Rouschop, Jeng-Jer Shieh, Maria Angeles Mena, Mei Zhao, Sonia Rocha, Xin Wen, Sylvain Lefort, Michael Scharl, Ramnik J. Xavier, Alan Cheng, Marion Bouchecareilh, Stella Y. Lee, Maria Xilouri, Qi Chen, Claudia Spies, Pengfei Ge, Natascia Ventura, Luca Galluzzi, Yau Hung Chen, Jing Pu Zhang, Diego Albani, Dingzhong Tang, Nikolai Engedal, Stefania Meschini, Maria Lyngaas Torgersen, Shibu M. Poulose, Jean-Paul Decuypere, Ziheng Xu, Jocelyn Laporte, Thierry Arnould, Albert Haas, Ida J. van der Klei, Agustín Hernández, Dong Wook Shin, Per E. Stromhaug, Valentín Ceña, Ugo Pagnini, Karolina Pakos-Zebrucka, Blagovesta Popova, Lisa M Lindqvist, Sangita C. Sinha, Yuguang Shi, Zvonimir Marelja, Robin Candau, Xin Wang, Evelina Gatti, Olatz Pampliega, Michael P. Lisanti, Elena Tamagno, Mei Lan Tan, Gary Warnes, Zdena Palková, Shigeomi Shimizu, Ingo Schmitz, Tino Kurz, Soledad Matus, Gopal Chakrabarti, Joseph J.Y. Sung, Beáta G. Vértessy, Giuliana Cassinelli, Giovanni Benard, Yin Chen, Emma Colucci-Guyon, Craig Blackstone, Lizhi Cao, Sebastian Schuck, Qingqiu Gong, Theocharis Panaretakis, Jayoung Choi, Sven R. Carlsson, Libuše Váchová, Raymond Chuen-Chung Chang, Yang Liu, Zheng Dong, Qinghua Shi, Hélène Duez, Tiziana Bachetti, Axel H. Schönthal, Sumit Sahni, Bo Wang, Naomichi Matsumoto, Markus Rehm, Liliana Torosantucci, Toren Finkel, Yi Hsin Tseng, Hsiang Cheng Chi, Fang Lin, Tony George Jacob, Ju-Xian Song, Alessandro Fanzani, Marc Tatar, Paola Costelli, Rubén Gómez-Sánchez, Yunfei Wen, Juha J. Hulmi, Francesca V. Mariani, Min Zeng, Chiung Chyi Shen, Carine Michiels, Yan Burelle, Andreas L. Serra, Goran Petrovski, Kwang Woon Kim, Paula Ludovico, Darius Ebrahimi-Fakhari, Yee Joo Tan, Luisa De Martino, Alvaro Glavic, Pierre Lapaquette, Edmund B. Rucker, Andreas Mayer, Shigeko Yamashiro, Scott K. Powers, Robert M. Gogal, Ebru Goncu, Yuichiro J. Suzuki, Anna Maria Giammarioli, Claudio Hetz, Eric H. Baehrecke, Cheryl L. Walker, Cinzia Lanzi, Deepti S. Wilkinson, Ralph Feuer, Long Yi, Virawudh Soontornniyomkij, Nektarios Tavernarakis, Nobuyuki Nukina, Elisabetta Ferraro, Thomas Wollert, Vassiliki Karantza, Simon Wilkinson, Yong Tae Kwon, Panagiotis D. Velentzas, Jong-In Park, Huu Phuc Nguyen, Miriam J. Schönenberger, Marcello Chieppa, Thomas A. Ferguson, Behzad Yeganeh, Saurabh Chatterjee, Anika Nagelkerke, Ju Hong Jeon, David W. Russ, Jeff W. Chen, Verónica I. Dumit, Chuangui Wang, Stephen C. Pak, Georgios Chamilos, Vijittra Leardkamolkarn, L. Ashley Cowart, Miguel A. Martín-Acebes, Andrea Cossarizza, László Orosz, X. Charlie Dong, Kei Watase, Yasuko Rikihisa, Santiago Rodríguez de Córdoba, Yu Jen Chen, Andrew P. Lieberman, Peter G.H. Clarke, Guylène Page, Babak Razani, Franziska Wild, Guang Zhou Zhou, Tsui-Fen Chou, Gen Sheng Wu, Daniel Johnson, Jiwu Wei, Rani Ojha, Marco Molinari, Manolis Fanto, Yongjun Jiang, Nadine Camougrand, Rong-Rong He, Ivan Dikic, Candece L. Gladson, Naoki Suzuki, Shiming Liu, Felipe X. 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Gibson, Chunlai Wu, Kai Kaarniranta, Paloma B. Liton, Feng Jun Li, Roberta Nardacci, Ernst J. Wolvetang, Robert C. Bast, Mark S. Cragg, Quentin Liu, Massimo Federici, Hyun Kyu Song, Hua Bai, Xiaotao Li, Nils J. Færgeman, Jason Chesney, Shrawan Kumar Singh, Marcello D'Amelio, Mark Prescott, Georg Auburger, Shazib Pervaiz, Allen Taylor, Diane C. Bassham, Lei Wan, Michinaga Ogawa, Emilia Maellaro, Cynthia Y. He, Chris Jones, Paolo Grumati, Jun-Lin Guan, Hiroyasu Nakano, Eric A. Schon, Roswitha Krick, Yoshihiro Shidoji, Jaime L. Schneider, Dusica Maysinger, Thomas Thum, Paul G. Thomes, Edo Vellenga, Liang Liu, Giuseppe Filomeni, Niramol Savaraj, Rudolf A. Kley, Wei Jung Chen, Bradley L. Baumgarner, Victor H. Villar, Steven Finkbeiner, Kapil Sirohi, Francesco Cecconi, Steven S. Witkin, Steve Jean, André du Toit, Rossella Russo, Irina Petrache, Randy Schekman, Keisuke Hino, Wei Chen, Basil J. Petrof, Daniel E. Frigo, Gyun Min Lee, Paul N. 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Gonzalez, Hong Zhang, Alkesh Jani, Heidi Kiil Blomhoff, Wen-Li Chen, Simon Sedej, François Bertrand Favier, Marina K. Holz, Mitsunori Fukuda, Gudmundur Vignir Helgason, Fu-Cheng Lin, Inés Díaz-Laviada, Stefaan J. Soenen, Chao Yung Wang, Chee Yin Chai, Pierre-André Bédard, Xiaoxiang Zheng, Peter V. Bozhkov, Han-Ming Shen, Hazel M. Davey, Pedro A. Lazo, Haoxing Xu, Fengtian He, Jean Max Pasquet, Benoit Pasquier, William T. Jackson, Stéphane Duvezin-Caubet, Bertrand Mollereau, Tomohiro Kabuta, Maria Rosa Ciriolo, Peter Hasselblatt, Nihar Ranjan Jana, Jane L. Armstrong, Elisa Giovannetti, Fang Lin Sun, Zhenyu Yao, Shuji Kishi, Pei-Hui Lin, Yingmei Zhang, Limor Avrahami, Kenichi Shibuya, Guillaume Dalmasso, Radovan Vasko, Sharon Prince, Valerie B. O'Donnell, Gordon B. Mills, Hiroshi Aoki, Maryam Mehrpour, Muniswamy Madesh, Guillermo Díaz-Araya, Susan L. Cotman, Marius K. Lemberg, Tilman Grune, Jing Lan Liu, Richard C. Wang, Sandro Goruppi, Hongmin Wang, Robert A. Heinzen, Xiangmei Chen, Nihal Altan-Bonnet, Sung Sik Lee, Hai Jie Wang, Catherine Dargemont, Jie Du, Sofie Claerhout, Edmond Chan, Yi Sun, Xiangbo Wan, Paul Lingor, Shilpa Buch, Gerald M. McInerney, Zhenlong Wu, Guo Chang Zhang, Iain A. McNeish, Suresh Awale, Mark P. Mattson, Srinivasa Subramaniam, Wuhan Xiao, Katsuhiko Mikoshiba, Giancarlo Parenti, Bruno Miguel Neves, Benjamin Dehay, Fatima Teixeira-Clerc, Patricia Huebbe, Calvin K. Yip, Ryan J. Schulze, Pallabi Sarkar, Vladimir I. Titorenko, Johanna Laukkarinen, Martin E. Gleave, Veronika Stoka, Pascal Genschik, Karen Brown, Zhaoliang Su, Walter Malorni, Arlette Darfeuille-Michaud, Vincent C. O. Njar, Jeffrey E. Pessin, Thomas Wileman, Alexander J. Whitworth, Stefano Santaguida, Gustavo A. Nader, Gláucia Maria Machado-Santelli, Marie-Josée Hébert, Skye C. McIver, Scott A. Soleimanpour, Jia-Hong Lu, Fei Liu, Yu Wang, Elisa Motori, Chad A. Dickey, Andrej Udelnow, Ahmed Hamaï, Junying Yuan, Jan Paul Medema, Michelangelo Campanella, Abhishek D. Garg, Pallavi Chandra, Marco Mongillo, Bonnie Bartel, Thomas Weide, Yong Joon Chwae, Nancy Y. Ip, Yoshiaki Kamada, Hikmet Budak, Jian Xiao, Mario D. Cordero, Wei Li, Muzamil Majid Khan, He Jin Lee, Meng-Chao Yao, Zu-Hang Sheng, Perrine Castets, Dongsheng Cai, Morten Petersen, Javier Díaz-Nido, Yong Lin, Kaio Kitazato, Yotaro Izumi, Beatrice Y.J.T. Yue, Des R. Richardson, Chunsun Dai, Michael Hensel, Ronit Sagi-Eisenberg, Chan Ding, Christian Sell, Idil Orhon, Wilhelm Krek, Qutayba Hamid, Salem Chouaib, Rajkumar Banerjee, Hsing Yu Tuan, Eyleen J. O’Rourke, Fathia Mami-Chouaib, Ryo Ushioda, Hidekazu Suzuki, Jie Fan, Anders H. Lund, Urban Emmenegger, Brigit E. Riley, Andrew Thorburn, Kailash Gulshan, Karol Dokladny, José M. Cuezva, Daniel T. Ruan, Salik Hussain, Mohamed Rahmani, Maria Teresa Bassi, Miquel Vila, Pavel Strnad, Terry H. Landowski, Christiaan Leeuwenburgh, Hagit Eldar-Finkelman, Francesco Fornai, Vincent Kam Wai Wong, Hengyi Xiao, Massimo Nabissi, Luciano Merlini, Chris Williams, Jatin M. Vyas, Motoko Sasaki, Chwen Ming Shih, Saveria Aquila, Marina Garcia-Macía, Po Wu Gean, Yasuo Kitajima, Gian Luigi Russo, Tania Zaglia, Arnaud Moris, Alessandra Stacchiotti, Elaine Gutierrez, Iain D. C. Fraser, Paolo Salomoni, Ramón Corbalán, Dave Bridges, Juan P. Liuzzi, Rosanna Parlato, Sandrine Silvente-Poirot, Carl G. Maki, Patty J. Lee, Paulo Pereira, Vitaliy O. Kaminskyy, Rajaraman Eri, Bertha Brodin, Tobias Eisenberg, Rong Yu Liu, Yide Mei, Pearl P.Y. Lie, Bradford G. Hill, Yoshio Fujitani, Angelika A. Noegel, Nadarajah Vigneswaran, Muriel Mari, Steven Grant, Davide Romanelli, Lee Ann MacMillan-Crow, Anna-Lena Ström, David Sulzer, Aditya Murthy, Lisa B. Frankel, Yong Ma, Ok-Nam Bae, Pablo Wappner, Chun Hei Antonio Cheung, Young Hyun Yoo, Andreas Linkermann, Kirill V. Rosen, Orsolya Kapuy, Simone Di Paola, Thomas J. Evans, Rosa A. González-Polo, Jin H. Son, Kinya Otsu, Tracey R. O’Donovan, Nicolas Pallet, Stefano Toldo, Wafik S. El-Deiry, Allen Kaasik, Jin Tai Yu, Susu M. Zughaier, Gordon W. Laurie, Barbara Guerra, Taeg Kyu Kwon, Priyamvada Dua, Stephen A. Spector, Yingyu Chen, Ayesha N. Shajahan-Haq, Wei Pan, Matthew Campbell, Leo A. B. Joosten, J. Paul Taylor, Julian J. Lum, Matthew J. Justice, Clarissa von Haefen, William K.K. Wu, Gerald Rimbach, Peter Polčic, Jens Schmidt, Saverio Bettuzzi, Xian De Liu, Satoru Kobayashi, Yan Zhang, Ling Tian, Péter Nagy, Mercedes Pozuelo-Rubio, Cheng Jin, Marek Los, Hiroyuki Ishida, Yuji Moriyasu, Maria Teresa Cruz, Jingjing Liu, Anil K. Sood, Roberto Mateo, Antonio Facchiano, J. Mark Cooper, Xiaofeng Yao, Pei Ming Yang, Eli Arama, Marc Diederich, Luc J. W. van der Laan, Robin Ketteler, James Harris, Eui Ju Choi, Grant R. Campbell, Julie D. Atkin, Janos Kriston-Vizi, Sharon L. McKenna, Mila Ljujic, Hirotaka Watada, Harry Ischiropoulos, Shile Huang, Udo Hasler, Ke Li, Josefina Casas, Ken-ichi Isobe, Min Li, Muriel Priault, Vincenzo De Tata, Monique Gannagé, Sakineh Kazemi Noureini, Isao Ishii, Sasanka Ramanadham, Valérie Pierrefite-Carle, Chengyu Liang, Louise Deldicque, Gabriella Cavallini, Afshin Samali, Angelika Amon, Kah-Leong Lim, Lavinia Cantoni, Demetrios G. Vavvas, James E. Haber, Alireza R. Rezaie, Regina Celia Bressan Queiroz de Figueiredo, Cynthia D. Cooper, Masaaki Komatsu, Silvia Alvarez, Gemma Triola, Dong-Yun Ouyang, Razaul Karim, Kostyantyn V. Dmytruk, Bassam Janji, Peter Bütikofer, Indira U. Mysorekar, Hana Popelka, E. Marion Schneider, Carlos Guillén, Gaël Roué, Seung-Hoon Baek, Patrick Auberger, Jun Araya, Sandra M. Cardoso, Gu He, Eduardo C. Filippi-Chiela, Patrick A. Lewis, Wei-Pang Huang, Eric Reits, Cécile Vindis, Trond Lamark, Mehrdad Alirezaei, Takao Setoguchi, Alberto Bartolomé, Chih Peng Chang, Andriy A. Sibirny, Mauro Piacentini, Jing Wang, Kuninori Suzuki, Ludo Van Den Bosch, Kevin N. Dalby, Keiran S.M. Smalley, David K. Ann, Luis F. Moita, Anthony Sanchez, Chin Hsu, Guillermo M. Albaiceta, Vassilis Stratoulias, Attila L. Kovács, Charleen T. Chu, Tewin Tencomnao, Audrey H. Poon, Steve Lancel, José C. Fernández-Checa, Hannah Rabinowich, Heinz D. Osiewacz, Sami Dridi, Kate E. Keller, Thorsten Hoppe, Crispin R. Dass, Jekaterina Erenpreisa, Akira Matsuura, Donna D. Zhang, Ying Zhao, Luisa Coletto, Roy Parker, Georg M. N. Behrens, Alessia Di Nardo, Mian Wu, Alberto Jiménez, Magdalena Rost-Roszkowska, Christopher J. H. Elliott, Pamela J. Yao, Damián Gatica, Rafael Linden, Helena L. A. Vieira, Anand K. Ganesan, Wim Martinet, Frank Madeo, Juliann G. Kiang, Helmut Kramer, Lorrie A. Kirshenbaum, Salvador Ventura, Clemens Steegborn, Zahra Zakeri, Marco Antonio Meraz-Ríos, Masaki Ohmuraya, Michael A. Riehle, Congcong He, Federica Sotgia, Shi-Mei Zhuang, Paul Dent, Jürgen Bosch, Xuejun Wang, Kuan-Chih Chow, Carlos Gorbea, Lisa Gerner, Yuzuru Imai, Jan Gunst, Duncan R. Smith, María Esther Pérez-Pérez, N. Tony Eissa, Michel Roberge, Carmen García-Ruiz, Irfan J. Lodhi, Hongjiao Ouyang, Mustapha Kandouz, Alessio Papini, Jun Sun, Takanobu Otomo, David H. Perlmutter, Jae-Sung Kim, Feng Gao, Åsa B. Gustafsson, Paul M. Salvaterra, Michael Klinkenberg, Or Kakhlon, Abhinav Diwan, Takahiro Shintani, Paola Matarrese, Marc D. Meneghini, Jinsheng Zeng, Xu-jie Zhou, Linda S. Yasui, Rui Sheng, Shiqian Huang, Elizabeth Delorme-Axford, Amélie Bernard, Kevin M. Ryan, Cecília M. P. Rodrigues, Jonathan M. Backer, Harald Stenmark, Hiroaki Adachi, Koichi Sakakura, Fatima Mechta-Grigoriou, Zhi Nong Wang, Ramesh Natarajan, Tian Xia, Marco Folini, Robert A. Screaton, Jane J. Yu, Xian Wang, Gerhard H. Braus, Min Wu, John A. Hanover, Anuj Kumar, Charbel Moussa, Shailendra Anoopkumar-Dukie, Edward A. Fon, Ted Powers, Thomas H. Kawula, Zhe Liu, Jennifer Martinez, Orian S. Shirihai, Mara Cirone, Fen Wang, Machiko Sakoh-Nakatogawa, Yong Xia, Durga Nand Tripathi, James T. Handa, Nadia Zaffaroni, Esther Wong, Carlos López-Otín, Michael E. Cheetham, Harm H. Kampinga, Leopold Eckhart, Paul de Figueiredo, Xueqin Liu, Michael S. Goligorsky, Valentina Sica, Marco Sandri, Wen Qiang Chen, Szabolcs Takáts, Lilach O. Lerman, Akio Kihara, Constantinos Koumenis, Sergio Comincini, Antoinette Lemoine, Marc Bitoun, Zhuo-Wei Hu, Yu Xiong Su, Jeremy C. Mottram, Miguel A. Sanjuan, Richard D. Vierstra, Angelo De Milito, Marjolein van Egmond, Xi-Long Zheng, Kun-Liang Guan, Katrin Juenemann, Ohkmae K. Park, Eisuke Itakura, Bo Yan, Tim Lahm, Yongshun Chen, Kenneth L. van Golen, Federica Rizzi, Guochang Hu, Volker Doetsch, Chengtao Her, Conrad C. Weihl, Jing Hsiung James Ou, Chiou Feng Lin, Dun-Sheng Yang, Bozena Gabryel, Xiao Feng Zhu, Jackie de Belleroche, Charles L. Edelstein, Julie Gavard, Miklós Sass, Maria Chiara Maiuri, Zhendong Zhao, Pu Duann, Julián Pardo, Atsuhiro Ichihara, Lester M. Davids, Swamynathan Ganesan, Shengyun Fang, Hernando Gomez, Yun Chau Long, Mark J. Czaja, Arnaud Echard, Pilar Gonzalez-Cabo, Chuanyong Guo, Katherine L. Cook, Isabel Varela-Nieto, Li Yu, Yi Ran Huang, Binfeng Lu, Athanassios D. Velentzas, Koji Yamanaka, Giuseppe Russo, Ester M. Hammond, Kelsey B. Law, Sheng Li, Samisubbu R. Naidu, Michael E. Boulton, Anna-Mart Engelbrecht, Ba-Bie Teng, Zixu Mao, Vania M.M. Braga, Núria S. Coll, Eliana M. Coccia, Akihisa Abe, V. Ashutosh Rao, Nava Segev, Regina Menezes, Zufeng Ding, Hyman M. Schipper, Álvaro F. Fernández, Peter K. Kim, Lucia Micale, Biplab Dasgupta, Nazzy Pakpour, Janna L. Morrison, Yue Qin Chen, Rolf J. Craven, Zvulun Elazar, Anders Aune Tveita, Lian Li, Hsueh Fen Juan, Ulrich Koenig, Qiang Shi, Harald W. Platta, Michele S. Swanson, Olga V. Voitsekhovskaja, Bruce H. 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Murphy, Isabelle Coppens, Luc Dupuis, Elio Ziparo, Patrick J. Bednarski, Svetlana Saveljeva, Ashok Kumar, Hongxin Zhu, Tobias B. Huber, Günther Weindl, Claudine Kraft, Dhiraj Kumar, Sara Marinelli, Karin von Schwarzenberg, Lijun Jia, Tiziana Crepaldi, Ke Liu, Eleonora García Véscovi, Qing Lu, Cláudia N. Santos, Bertrand H. Rihn, Jun Yu, Fen-Biao Gao, Flavio Flamigni, Jason E. Gestwicki, Dong-Hun Bae, Gustavo C. MacIntosh, David A. Leib, Giorgio Santoni, Chin Yuan Hsu, Abdelhaq Rami, Joseph Satriano, Matthew J. LaVoie, Paloma Martín-Sanz, Daniela De Zio, Sharon M. Gorski, Yu Tian Wang, Shuyan Lu, Clara L. Oeste, Andrew R. Tee, Koji Itahana, Xuesong Yang, Shuiping Tu, Malathi Krishnamurthy, Anne M. Strohecker, Gui Xian Xia, Helena Orozco, Sujit K. Bhutia, Hongbo Hu, Rupert Beale, Ying-Ray Lee, Kai Mao, Pierre-Emmanuel Rautou, Jean Francois Groulx, James A. Mastrianni, Victoria El-Khoury, Koji Okamoto, Mark J. Taylor, Arianna L. Kim, José M. Izquierdo, Dalibor Mijaljica, Björn Stork, Thomas Schwarz, Savita Bhalla, Menno van Lookeren Campagne, Long Zhang, Elizabeth S. Yeh, Li Zhang, Tae Cheon Kang, Frederic Luciano, Shusaku Shibutani, Luciana Dini, Valentina Cianfanelli, Sara Calatayud, Yong-Sun Kim, Maurizio Molinari, Graham H. Coombs, Takeshi Noda, Angelo Poletti, Silvia Palumbo, Dhan V. Kalvakolanu, Valérie Vouret-Craviari, Volodymyr Y. Nazarko, Salvatore Florio, Noboru Mizushima, Arthur Kaser, Shigeki Miyamoto, Patric J. Jansson, Thomas I-Sheng Hwang, Daniel J. Jackson, Adrian L. Harris, Srikanta Dash, Yeong Min Yoo, David Colecchia, Ute C. Meier, Yi Ma, Tadashi Suzuki, Anand Krishnan V. Iyer, Flavia Radogna, Paul S. Brookes, Deepak Kumar, Gabriella D'Orazi, Barry Yedvobnick, David R. Soto-Pantoja, Christian Waeber, Craig McCormick, Dong Hu, Sarron Randall-Demllo, Gustavo J.S. Pereira, Emil Rudolf, Scott L. Friedman, Paolo Bonaldo, Oliana Carnevali, Guido R.Y. De Meyer, Alice Carrier, Yipeng Wang, Serena Montagnaro, Nadeem O. Kaakoush, José de la Fuente, Devrim Gozuacik, Edward D. Plowey, Alastair M. Buchan, John C. Chatham, Daniel J. Klionsky, Cecilia Gotor, Isabelle Hamer, Katarzyna Mnich, Paola Rusmini, Chengshu Wang, Per Nilsson, Lorena Esteban-Martínez, Raúl V. Durán, Dieter Willbold, Hye Won Chung, Janet D. Sparks, John M. Lucocq, Blake B. Rasmussen, Takeshi Matsuzawa, Hagai Abeliovich, Wiep Scheper, Sung Joon Lee, Jennifer S. Carew, Serena Carra, Michael J. Morgan, Nikolai Slavov, Guy Berchem, Tiziana Cocco, Simone Engelender, Jianbo Yue, Yujie Chen, Mario Fabri, Maria F. Czyzyk-Krzeska, Hua Niu, Roger J. Davis, Peter J. Adhihetty, Kishore B.S. Pasumarthi, Jongsook Kim Kemper, Sharon A. Tooze, Antonio Zorzano, Jin Cheon Kim, Jian Xu, Andreas Meryk, Kristina Vuori, Jongdae Lee, Patrizia Agostinis, Diego Ruano, Wim Vandenberghe, Julia I-Ju Leu, Céline Gongora, Bernadette Carroll, Vinoth Kumar Megraj Khandelwal, Bo Lu, Marja Jäättelä, Lorenzo Galluzzi, Ioannis P. Trougakos, Tatsuya Maeda, Marie-Agnès Bringer, Mario Chiong, Hans-Uwe Simon, Lance A. Liotta, Ruth S. Slack, Ina Oehme, Umamaheswar Duvvuri, Shaun Martin, Augustine M.K. Choi, Michel Vidal, Ying Wang, Isis do Carmo Kettelhut, Mojgan Djavaheri-Mergny, Jörn Coers, Massimo Donadelli, Jesus Aldudo, Miyuki Sato, Jianxun Liu, Jörg Höhfeld, Luc Van Kaer, Andrei I. Ivanov, Dohun Pyeon, José M. Bravo-San-Pedro, Jianxin Peng, Xiaoyan Jiang, Dimitri Krainc, Yangqing Xu, Arnaud François, P. Robin Hiesinger, Sagar Lonial, William C. Cho, Caty Casas, Betty Yuen Kwan Law, Hongbing Zhang, Tor Erik Rusten, Erwin Knecht, Honglin Luo, Shi Xiao, Hiromi Sesaki, Enza Maria Valente, Verónica Pérez de la Cruz, Marta M. Lipinski, David A. Hood, Shi-Yong Sun, Luiz Carlos Carvalho Navegantes, Joynal Abedin, Shino Goto-Yamada, Gustavo Maegawa, Takehiko Matsushita, Vitor A. Lira, Clara I. Rodríguez, Ekihiro Seki, Qiang Li, Karin Öllinger, Ted M. Dawson, Ssang-Goo Cho, Wan-Wan Lin, Pramod Kumar Garg, Jeffrey Robbins, Peter R. Williamson, Michael Sacher, Carlo Follo, Bulent Ozpolat, Xiao Jia Wang, Na Man, Hua Cheng, Bing Yan, Tsung-Hsien Chuang, Paul B. Fisher, Rajat Singh, Edward A. Ratovitski, Katsuhiko Kitamoto, Jung Jin Hwang, Shinji Hadano, Che Hsin Lee, Shuo Wang, Einar M. Sigurdsson, Camille Martinand-Mari, Agnieszka Sirko, Katherine R. Parzych, Etienne Morel, Yasushi Kitaoka, Hassan Chaachouay, Patricia Chakur Brum, Dexin Kong, Jerome Tamburini, Kuppan Gokulan, Stefan Olsson, Bilon Khambu, Lea M.D. Delbridge, Daniel P. Orban, David A. Gewirtz, Zhonglin Xie, Joe Quadrilatero, Kunikazu Tanji, Simin Mohseni, Gábor Bánhegyi, Jin Ming Yang, Jinxian Xu, Carmen Veríssima Ferreira-Halder, Addanki P. Kumar, Deok Ryong Kim, Jianjie Ma, Sang Won Suh, Guido Kroemer, Klára Megyeri, Michael N. Sack, Heinrich Taegtmeyer, Gilles Pagès, Gabriella Marfe, Gregg L. Semenza, Karine G. Le Roch, Marisa Brini, Marina Bouché, Oliver Kepp, Vinay V. Eapen, J. David Beckham, Stephan T. Stern, Xudong Zhang, Marcello Pinti, Xiangnan Zhang, Jae Keun Lee, Ana Coto-Montes, Assaf Rudich, Laura D. Attardi, Debabrata Ghosh, Philip Rosenstiel, Sébastien Besteiro, Maria Rosa Sarrias, R. Andres Floto, Xiao Ming Yin, Nicholas W. Lukacs, Hermann Pavenstädt, Matias Simons, Hitoshi Nakatogawa, Sandro Alves, Krisztina Takács-Vellai, Masato Koike, Debasish Sinha, Shoji Notomi, Faraj Terro, Maria Carmela Roccheri, Santiago Ambrosio, K. Ulrich Bayer, Yumin Li, Terje Johansen, Christian Kuhn, Yee Shin Lin, David C. Rubinsztein, Ziwei Qu, Ronit Shiri-Sverdlov, Emmanuel T. Akporiaye, Galila Agam, Hui Ling Chiang, Seung-Jae Lee, Yu Xue, Francesca Giampieri, Markus Damme, Tassula Proikas-Cezanne, Tianwei Lin, Marc Kantorow, Guang-Chao Chen, Qiangrong Liang, Claudia Manzoni, Joan S. Steffan, Emilio Boada-Romero, Damien Freyssenet, Sepp D. Kohlwein, Maria D. Barrachina, Yulin Liao, Jiankang Chen, Erika Isono, Hugo Seca, Mei Wang, Taras Y. Nazarko, Yannick Bailly, Nadya V. Koshkina, Tapas K. Maiti, Bärbel Rohrer, Karin Nowikovsky, James H. Hurley, Gerald W. Dorn, Nils C. Gassen, Kazuhiro Nagata, Eiki Kominami, A. Ivana Scovassi, Ana Maria Cuervo, Adi Kimchi, Minghua Yang, Sylviane Muller, Life Sciences Institute and Department of Molecular, Cellular, and Developmental Biology and Biological Chemistry, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Defense in Plant-Pathogen Interactions [Nagoya, Japan], Nagoya University-Graduate School of Bioagricultural Sciences [Nagoya, Japan], Facultad de Quimica [Santiago], Pontificia Universidad Católica de Chile (UC), Institute of Cancer Sciences [Glasgow, UK] (CR-UK Beatson Institute), University of Glasgow, Cell Death Research & Therapy (CDRT) Lab, Université Catholique de Louvain, Harvard University Statistics Department, Harvard University [Cambridge], Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Conway Institute of Biomolecular and Biomedical Research and School of Chemical and Bioprocess Engineering, University College Dublin [Dublin] (UCD), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Biochemistry and Molecular Biology, Thomas Jefferson University-Sidney Kimmel Cancer Center, Jefferson (Philadelphia University + Thomas Jefferson University)-Jefferson (Philadelphia University + Thomas Jefferson University), Centro de Estudios Farmacológicos y Botánicos [Buenos Aires] (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET)-Facultad de Medicina [Buenos Aires], Universidad de Buenos Aires [Buenos Aires] (UBA)-Universidad de Buenos Aires [Buenos Aires] (UBA), Thérapie génique, Génomique et Epigénomique (U 1169), Université Paris-Saclay-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11), Department of Experimental Medicine and Public Health, University of Camerino, MRC Toxicology Unit, University of Leicester, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Departamento de Bioquímica y Biología Molecular y Celular, University of Zaragoza - Universidad de Zaragoza [Zaragoza], Department of Pharmaco-Biology, Università della Calabria [Arcavacata di Rende] (Unical), Department of Molecular Genetics [Rehovot, Israël], Weizmann Institute of Science, Fondation Universitaire Notre Dame de la Paix (FUNDP), Facultés Universitaires Notre-Dame de la Paix, Département Advanced Research And Techniques For Multidimensional Imaging Systems (ARTEMIS), Institut Mines-Télécom [Paris] (IMT)-Télécom SudParis (TSP), USC Neuromuscular Center, Department of Neurology, University of Southern California (USC), Centre méditérannéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Giannina Gaslini Institute, Department of Molecular Pharmacology, Albert Einstein College of Medicine, Department of Cancer Biology, University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS)-University of Massachusetts System (UMASS), Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École pratique des hautes études (EPHE)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), Inner Mongolia Agricultural University (IMAU), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Franche-Comté (UFC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Technologie de Belfort-Montbeliard (UTBM), Indian Institute of Science [Bangalore] (IISc Bangalore), Politecnico di Milano [Milan] (POLIMI), Département des Sciences Biologiques [Montréal], Université du Québec à Montréal (UQAM), Laboratory of Molecular Biology, Scientific Institute E. Medea, Université Catholique de Louvain (UCL), Univ Ancona, Politecn Marche, University of Toronto, Munich Cluster for systems neurology [Munich] (SyNergy), Technische Universität München [München] (TUM)-Ludwig-Maximilians-Universität München (LMU), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Department of Clinical and Molecular Medicine, Università degli Studi di Roma 'La Sapienza' [Rome]-Réseau International des Instituts Pasteur (RIIP)-Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP), Physiopathologie du système nerveux central - Institut François Magendie, Université Bordeaux Segalen - Bordeaux 2-IFR8-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Hémato-Cancérologie Expérimentale, CRP-Santé, Dpt of Neuroscience and Brain Technologies [Genova], NeuroEngineering & bio-arTificial Synergic SystemS Laboratory [Genova] (NetS3 Lab), Istituto Italiano di Tecnologia (IIT)-Istituto Italiano di Tecnologia (IIT), Center for Infection and Immunity Amsterdam (CINIMA), Laboratoire de biogenèse membranaire (LBM), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Régulation de l'expression génétique (REG), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris)-Centre National de la Recherche Scientifique (CNRS), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Department of Microbiology and Immunology, Stanford University School of Medicine [CA, USA], Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Department of Dermatology, Brigham and Women's Hospital [Boston], San Raffaele Scientific Institute, Milan, Italy, Laboratory of Molecular Neuroembryology, University of Rome 'Tor Vergeta'-Clinical and Behavioral Neurology - Neuroscienze e riabilitazione, IRCCS Fondazione Santa Lucia [Roma]-Dulbecco Telethon Institute, Department of Pharmacology, Universidade de Santiago de Compostela, Glycobiologie et signalisation cellulaire, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Complexo Hospitalario Universitario A Coruña, Mécanismes moléculaires de l'angiogénèse, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Florida [Gainesville], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U1172 Inserm), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Centro de Investigaciones Biológicas (CSIC), Consejo Superior de Investigaciones Científicas [Spain] (CSIC), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (HOTE GREFFON), Université de Franche-Comté (UFC)-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Infection bactérienne, inflammation, et carcinogenèse digestive, Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Universita degli Studi di Padova, University of British Columbia (UBC), University of Edinburgh, Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), Australian Regenerative Medicine Institute, Monash University, Clayton, 3800, VIC, Australia, Faculty of Engineering and Natural Sciences, Sabanci University [Istanbul], Department of Biological Sciences [Stanford], Stanford University [Stanford], Université de Montréal (UdeM), Department of Human Genetics, Department of Psychiatry, University of Michigan System-University of Michigan System-Molecular and Behavioral Neuroscience Institute, Centre for Computational and Systems Biology (COSBI), Department of Computer Science [Tsukuba], Graduate School of Systems and Information Engineering [Tsukuba], University of Tsukuba-University of Tsukuba, Institut de biochimie et génétique cellulaires (IBGC), University of Western Ontario (UWO), Genetics, Dynamique Musculaire et Métabolisme (DMEM), Institut National de la Recherche Agronomique (INRA)-Université de Montpellier (UM), Department of Biochemistry and Biophysics, University of Naples Federico II, Lund University [Lund], Institute of Molecular Biosciences, Karl-Franzens University Graz, (IMB), Karl-Franzens-Universität Graz, Polytechnic University of Marche, Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Cell Biology, Physiology and Immunology, Research Unit on BioActive Molecules, Departamento de Química Orgánica Biológica, Instituto de Investigaciones Quimicas y Ambientales de Barcelona, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), The Buck Institute for Age Research, University of Pisa - Università di Pisa, Laboratorio di Genetica Molecolare, Istituto Gaslini, Universidad de Castilla-La Mancha (UCLM), Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, University of Crete [Heraklion] (UOC), Division of Molecular and Cellular Pathology [Birmingham], Department of Medical Research, Taichung Veterans General Hospital, Modélisation et Simulation Numérique en Mécanique et Génie des Procédés (MSNMGP), Université de la Méditerranée - Aix-Marseille 2-Université Paul Cézanne - Aix-Marseille 3-Université de Provence - Aix-Marseille 1-Centre National de la Recherche Scientifique (CNRS), University of Queensland [Brisbane], Dept of Mathematics, Purdue University, Purdue University [West Lafayette], Virologie et Pathologie Humaine (VirPath), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Zhejiang University, Équipe Micro et nanosystèmes HyperFréquences Fluidiques (LAAS-MH2F), Laboratoire d'analyse et d'architecture des systèmes (LAAS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J), King Abdullah University of Science and Technology (KAUST), Southern University of Science and Technology of China (SUSTech), OASE, National University of Tainan, Taiwan (OASE), National Taiwan University [Taiwan] (NTU), Weifang Bureau of Land Resources [Weifang], Department of cardiology [Guy's and St. Thomas ' hospitals] [London], Guy's and St Thomas' Hospital [London]-Guy's Hospital [London], University of Pennsylvania [Philadelphia], CRLCC Eugène Marquis (CRLCC), Emory University School of Medicine, Emory University [Atlanta, GA], Korea University, Cytokines et Immunologie des Tumeurs Humaines (U753), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pharmacology [Tartu, Estonie], Institute of Biomedicine and Translational Medicine [Tartu, Estonie], University of Tartu-University of Tartu, Max-Planck-Institut für Biophysikalische Chemie - Max Planck Institute for Biophysical Chemistry [Göttingen], Max-Planck-Gesellschaft, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), University of Cincinnati (UC), Réponses immunes : régulation et développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Experimental Medicine, Oxford University, University of Oxford [Oxford], Division of regenerative Medicine, San Raffaele Scientific Institute, The University of New Mexico [Albuquerque], Université Libre de Bruxelles [Bruxelles] (ULB), Macrophages et Développement de l'Immunité, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU)-Johns Hopkins University (JHU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Dipartimento di Scienze Biomediche, Università degli Studi di Modena e Reggio Emilia (UNIMORE), Department of Experimental Medicine and Oncology, University of Turin, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), CNV, University of Valparaiso, Institut Gustave Roussy (IGR), Universidad Autonoma de Madrid (UAM), Cell Signalling & Proteomics Group [Londres, Royayme-Uni], Barts Cancer Institute [Londres, Royayme-Uni], Queen Mary University of London (QMUL)-Queen Mary University of London (QMUL), Department of General, Visceral and Vascular Surgery [Jena], Friedrich-Schiller-Universität Jena, Department of Biomedical Engineering, The University of Texas at Austin, University of Texas at Austin, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte - Clermont Auvergne (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Fondazione Santa Lucia (IRCCS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Jacques Monod (IJM (UMR_7592)), Institute of Biological, Environmental and Rural Sciences (IBERS), Aberystwyth University, Department of Biology, Johns Hopkins University (JHU), Neurogenetics Group, Instituto de Investigación en Recursos Cinegéticos (IREC), Laboratório de Ultraestrutura Celular Hertha Meyer (IBCCF), Universidade Federal do Rio de Janeiro [Rio de Janeiro] (UFRJ), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich), Molecular and Cellular Biology, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), National University of Ireland [Galway] (NUI Galway), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Freiburg Institute for Advanced Studies-LifeNet, Albert-Ludwigs-Universität Freiburg, Groupe de Recherche en Immunopathologies et maladies infectueuses (GRI), Université de La Réunion (UR)-Centre hospitalier Félix-Guyon [Saint-Denis, La Réunion], Brunel University London [Uxbridge], Unité Propre de Recherche 2357, Institution de Biologie Moléculaire des Plantes, Radiothérapie moléculaire (UMR 1030), Department of Chemistry, University of Kentucky, Universidad de Córdoba [Cordoba], Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' [Rome], Facultad de Ciencias Químicas y Farmacéuticas, Centro de Estudios Moleculares de la Célula, Biochemistry and Molecular Biology, Goethe-University Frankfurt am Main, Department of Biological and Environmental Sciences and Technologies (DiSTeBA), Università del Salento, Institut Bergonié - Département de médecine, Université Bordeaux Segalen - Bordeaux 2-Centre régional de lutte contre le cancer [CRLCC], Institut National Polytechnique de Lorraine (INPL), Récepteurs nucléaires, maladies cardiovasculaires et diabète (EGID), Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Laboratoire de signalisation moléculaire et neurodégénerescence, Université Louis Pasteur - Strasbourg I-IFR37-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Européen de Chimie et Biologie (IECB), Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Trafic membranaire et Division cellulaire, Landesbetrieb Hessisches Landeslabor, Hematology-Oncology Division, Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], University of Pavia, Instituto de Investigaciones Biotecnológicas [San Martín] (IIB-INTECH), Universidad Nacional de San Martin (UNSAM)-Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET), University of Helsinki, School of Physics and Astronomy [Exeter], University of Exeter, Department of Biomedicinal Chemistry (CSIC), Institut de Química Avançada de Catalunya, Laboratory of Vascular Pathology (IDI-IRCCS), Istituto Dermopatico dell'Immacolata, Peking University [Beijing], MRC Centre for Developmental Neurobiology, University of Brescia, Immunobiologie fondamentale et clinique, Université de Lyon-Université de Lyon-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC régional épidémiologie clinique/essais cliniques - Ile de la Réunion (CIC-EC), University of Rome 'Tor Vergeta', Universidad de Oviedo [Oviedo], Laboratoire des signaux et systèmes (L2S), Université Paris-Sud - Paris 11 (UP11)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Dulbecco Telethon Institute/Department of Biology, Istituto Nazionale di Malattie Infettive 'Lazzaro Spallanzani' (INMI), Rockefeller University [New York], The Babraham Institute, Kansas State University, McGill University, Service d'Anatomie et Cytologie Pathologique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Department of Medicine [New York], Icahn School of Medicine at Mount Sinai [New York] (MSSM), ATOS Origin, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences-Tohoku University [Sendai], Goethe-University, Goethe-Universität Frankfurt am Main, Institute of physiological chemistry, Hannover Medical School [Hannover] (MHH), Department of Physiology, Department of Plant and Environmental Sciences, Apoptose, cancer et immunité (U848), Laboratoire de Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Departments of Neurology and Psychiatry, Alzheimer's Disease Research Center, Institute of Experimental Immunology - IEI [Zürich, Switzerland], Université de Zurich [Switzerland], Digital Enterprise Research Institute (DERI-NUIG), Spanish National Research Council (CSIC), Cell Death Research and Therapy Unit [Leuven, Belgium] ( Department of Cellular and Molecular Medicine), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Signaling in Oncogenesis, Angiogenesis and Permeability - SOAP (CRCINA - Département ONCO - Equipe 15), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Department of Medicine [San Francisco], University of California [San Francisco] (UCSF), University of California-University of California, Fondazione Santa Lucia [IRCCS], Clinical and Behavioral Neurology [IRCCS Santa Lucia], Institut de biologie moléculaire des plantes (IBMP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, INSB-INSB-Centre National de la Recherche Scientifique (CNRS), Department of Anatomy, Histology, Forensic Medicine and Orthopedic, N.A., Division of Pharmacology and Chemotherapy, Department of Internal Medicine, Pathogénie Microbienne Moléculaire, University of Chile [Santiago], Université de Montpellier (UM), Faculdade de Ciências Farmacêuticas de Ribeirão Preto [São Paulo], Universidade de São Paulo (USP), Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), Catalan Institute of Oncology, Department of Cell Biology, National Institute for Basic Biology [Okazaki], Instituto de Bioquímica Vegetal y Fotosíntesis (IBVF), Universidad de Sevilla-Centro de Investigaciones Científicas Isla de la Cartuja, The Adams Super Center for Brain Studies, Tel Aviv University [Tel Aviv], Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF)-Centre National de la Recherche Scientifique (CNRS), Department of Pharmacology and biochemistry, Virginia Commonwealth University (VCU), Department of Immunology, St Jude Children's Research Hospital, Department of Biology and Biotechnologies 'Charles Darwin', Lettres, Idées, Savoir (LIS), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institute of Biological Chemistry and Nutrition, University of Hohenheim, China Seismological Bureau, Massachusetts Institute of Technology (MIT), Rosenstiel Basic Medical Sciences Research Center [Waltham], Brandeis University, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA), Meakins-Christie Laboratories, Sanford Burnham Medical Research Institute, La Jolla, National Institute of Advanced Industrial Science and Technology (AIST), ORIENT ET MÉDITERRANÉE : Textes, Archéologie, Histoire (OM), Université Panthéon-Sorbonne (UP1)-École pratique des hautes études (EPHE)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Centro de Investigacion y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Biochemistry and Molecular Biology I, Department of Immunology and Infectious Diseases, Harvard School of Public Health, aDepartment of Plant Biology, Uppsala BioCenter, Swedish University of Agricultural Sciences (SLU), Philipps University of Marburg, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Renal Division, University Medical Center Freiburg, Freiburg, Germany, Rural Health Academic Centre, University of Melbourne-Rural Clinical School, Department of Pathology, University of Veterinary and Animal Sciences, Dipartimento di Scienze della Vita [Modena, Italy], Stress Cellulaire, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pathology, Anatomy & Cell Biology [Philadelphia, Pennsylvania, USA], Thomas Jefferson University, Department of Molecular Neuroscience, Departamento de Bioquimica Clinica, Facultad de Ciencias Quimicas, Centro de Investigación en Bioquímica Clínica e Inmunología (CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina, Neuroinflammation Unit, Biotech Research and Innovation Centre-University of Copenhagen = Københavns Universitet (KU), Mathematics and Computing in Automatic Control and Optimization for the User (MIAOU), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Danish Cancer Society, Institute of Cancer Biology, UCL-Institute of Child Health (ICH), Institute of Child Health-Great Ormond Street Hospital for Children [London] (GOSH), Division of Renal Diseases and Hypertension, University of Colorado [Boulder], Institut de biologie et chimie des protéines [Lyon] (IBCP), Joslin Diabetes Center, Universität Ulm - Ulm University [Ulm, Allemagne], Qingdao Institute of Marine Geology, China Geological Survey, Qingdao 266071, China, Université Paris Diderot - Paris 7 (UPD7), Institute of Software, Chinese Academy of Sciences [Beijing] (CAS), Metabolic Engineering Group, Departamento de Microbiologia y Genetica, Edificio Departamental, Campus Miguel de Unamuno, Universidad de Salamanca, University of Minnesota [Twin Cities], University of Minnesota System, Department of Cellular and Molecular Physiology, Yale University School of Medicine, The Arctic University of Norway, Department of Biological Sciences, The Open University [Milton Keynes] (OU), Summit Analytical, CALRG, Institute of Educational Technology, Institute for Neurologic Disabilities Research, Faculty of Health Sciences-University of Pretoria [South Africa], Department of Paediatric Neurology, Guy's and St Thomas' Hospital [London]-Evelina Children's Hospital, Physiologie des Adaptations Nutritionnelles [UMR_A1280] (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Dana-Farber Cancer Institute and the Department of Cell Biology, Harward Medical School, Translational Health Science and Technology Institute [Faridabad] (THSTI), Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands, School of Reliability and Systems Engineering [Beijing], Beihang University, Oxford Centre for Integrative Systems Biology, Center for Membrane and Cell Physiology [Charlottesville, VA, USA] (School of Medicine), University of Virginia [Charlottesville], Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Karlsruher Institut für Technologie (KIT), Faculty of Pharmaceutical Sciences, Hokkaido University, École normale supérieure - Paris (ENS Paris), School of Electrical Engineering [Seoul] (Korea University), Department of Mathematics and Statistics [Guelph], University of Guelph, Department of Molecular Genetics, Department of Genetics [Stanford, CA, États-Unis], Institute of Immunology, University Hospital Schleswig-Holstein, Arizona Respiratory Center, Okazaki Institute for Integrative Bioscience, ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Newcastle University [Newcastle], JRC Institute for Transuranium Elements [Karlsruhe] (ITU ), European Commission - Joint Research Centre [Karlsruhe] (JRC), Department of Neuroscience, University of Texas Southwestern Medical Center [Dallas], Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Laboratory of Functional Neurogenomics [Tuebingen, Germany], University of Tuebingen-Center of Neurology and Hertie-Institute for Clinical Brain Research [Tuebingen, Germany], Indian Institute of Technology Bombay (IIT Bombay), European Organization for Nuclear Research (CERN), Harvard Medical School [Boston] (HMS), Indian School of Mines, Department of Computer Science [UIUC] (UIUC), University of Illinois at Urbana-Champaign [Urbana], University of Illinois System-University of Illinois System, Centre for Cancer Biology, Hanson Institute, Adelaide, University of California [San Diego] (UC San Diego), University of California, Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Department of Biochemistry, University of Bristol, Organisation Nucléaire et Oncogenèse, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), FONDAP Center CEMC Estudios Moleculares de la Célula, Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Centre d'infectiologie Necker-Pasteur [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Chungnam National Univesity School of Medicine, Taejon, Korea, Chungnam National Univesity School of Medicine, Micro & Nanobiotechnologies, Institut des Sciences Analytiques (ISA), Centre National de la Recherche Scientifique (CNRS)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École normale supérieure - Lyon (ENS Lyon), Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de génétique moléculaire (CGM), Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Center for Applied Mathematics, Tsinghua University [Beijing], University of Connecticut School of Medicine, University of Connecticut (UCONN), Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes (LBMCE), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Microenvironnement et Physiopathologie de la Differenciation, Division of Nephrology and Hypertension, Mayo Clinic, Beatson Institute for Cancer Research, Beatson institute for cancer research, Howard Hughes Medical Institute, Howard Hugues Medical Institute, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Computing Technology [Beijing] (ICT), Chinese Academy of Sciences [Changchun Branch] (CAS), School of Electronics and Computer Science (ECS), University of Southampton, Third Hospital, Department of Anesthesiology, Cognitive Interaction Technology [Bielefeld] (CITEC), Universität Bielefeld = Bielefeld University, Procédés, Matériaux et Energie Solaire (PROMES), Université de Perpignan Via Domitia (UPVD)-Centre National de la Recherche Scientifique (CNRS), Faculty of Pharmacy- University of Coimbra, National Neuroscience Institute, Key Laboratory of Molecular Virology & Immunology (LMVI), Institut Pasteur de Shanghai, Académie des Sciences de Chine - Chinese Academy of Sciences (IPS-CAS), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Coll Life Sci, Beijing Normal University, Delft University of Technology (TU Delft), Christian-Albrechts-Universität zu Kiel (CAU), Department of Molecular Pathology and Microbiology, Center for Applied Proteomics and Molecular Medicine-George Mason University [Fairfax], Sidney Kimmel Cancer Center, Jefferson (Philadelphia University + Thomas Jefferson University), Institut des Sciences Chimiques de Rennes (ISCR), Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Rennes-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES), Department of Chemistry, University of Pittsburgh, University of Pittsburg, Tianjin University of Science and Technology (TUST), Hunan University of Science and Technology [Xiangtan], Laboratoire de Génie Civil et Génie Mécanique (LGCGM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), China Agricultural University (CAU), Acad Disaster Reduct and Emergency Management, Minist Civil Affairs, Minist Educ, Beijing, Peoples R China, affiliation inconnue, Département Technologie des Polymères et Composites & Ingénierie Mécanique (TPCIM), École des Mines de Douai (Mines Douai EMD), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Ministère de l'Economie, des Finances et de l'Industrie, MOE Key Laboratory of Bioinformatics, Centre for Plant Biology, School of Life Sciences, Laboratoire d'Informatique Gaspard-Monge (ligm), Université Paris-Est Marne-la-Vallée (UPEM)-École des Ponts ParisTech (ENPC)-ESIEE Paris-Fédération de Recherche Bézout-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biochimie Moléculaire et Cellulaire (LBMC), Université de Bourgogne (UB), Center for International Blood and Marrow Transplant Research (CIBMTR), Emory University [Atlanta, GA]-Medical College of Wisconsin, Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Illman Cancer Center, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Ingénierie des Matériaux Polymères (IMP), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA), Department of Medical Microbiology and Immunology, University of California [Davis] (UC Davis), School of Health Sciences, University of Minho [Braga], Équipe Calcul Distribué et Asynchronisme (LAAS-CDA), University of California [Riverside] (UCR), Ohio State University [Columbus] (OSU), Laboratory of Systems Biology, Van Andel Institute [Grand Rapids], Division of Genetics and Cell Biology, National Center for Gender-Specific Medicine, Istituto Superiore di Sanità, Oregon Health and Science University [Portland] (OHSU), Dendrite Differenciation Group [DZNE - Bonn], German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Equipe 12, Génétique moléculaire, signalisation et cancer (GMSC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University Medical Center [Utrecht], Institut d'Investigacions Biomèdiques August Pi I Sunyer [Barcelona, Spain] (Hospital Clinic ), Department of Genetics, Trinity College Dublin, Fisiopatologia de los procesos inflamatorios, Vall d'Hebron Research Institute, Institució Catalana de Recerca i Estudis Avançats (ICREA), Department of Human Genetics, Nagasaki University, Transduction du signal et oncogénèse, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie, Center for Experimental and Molecular Medicine, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), Department of medical Biochemistry, University of Amsterdam [Amsterdam] (UvA), IDI-IRCCS Biochemistry Laboratory, Università degli Studi di Roma Tor Vergata [Roma], Program Against Cancer Therapeutic Resistance/Metabolism & Cancer Group [Catalonia, Spain] (ProCURE), Catalan Institute of Oncology-Girona (ICO-Girona), Instituto de Tecnologia Química e Biológica António Xavier (ITQB), Universidade Nova de Lisboa (NOVA), Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza Hospital, CNR, Consiglio Nazionale delle Ricerche (CNR), Biochimie et Physiologie Moléculaire des Plantes (BPMP), Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, The Hospital for sick children [Toronto] (SickKids), Universidad de Sevilla, Immunité muqueuse et vaccination, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR50-Université Nice Sophia Antipolis (... - 2019) (UNS), DIMS, University of Trento [Trento], Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Department of Cellular and Molecular Medicine [Madrid, Spain], Laboratory of Cell Death and Cancer Therapy [Madrid, Spain], Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC) -Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Plymouth Marine Laboratory, Prospect Place, The Hoe, Plymouth PL1 3HD, UK, Centre d'Immunologie et de Maladies Infectieuses (CIMI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Dpt. of Cancer & Cell Biology, Interactions Bactéries-Cellules (UIBC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Institut National de la Recherche Agronomique (INRA), Max planck Institute for Biology of Ageing [Cologne], Euromov (EuroMov), Wellcome Trust Centre for Molecular Parasitology [Glasgow, UK], University of Glasgow- Institute of Infection, Immunity and Inflammation [Glasgow, UK], Immunologie et chimie thérapeutiques (ICT), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique (CNRS), UMR 1599, Centre National de la Recherche Scientifique (CNRS), EA 4100, Histoire culturelle et sociale de l'art (HiCSA), Université Panthéon-Sorbonne (UP1)-Université Panthéon-Sorbonne (UP1), Centre for Astrophysics and Supercomputing (Centre for Astrophysics and Supercomputing), Swinburne University of Technology [Melbourne], Department of Cellular and Physiological Sciences [Vancouver, BC, Canada] (Life Sciences Institute), University of British Columbia (UBC)-Life Sciences Institute [Vancouver, BC, Canada], School of Pharmacy, Department of Experimental Medicine, Dept. Neurosciences, Department of Internal Medicine, Radboud University Medical Center [Nijmegen], Institute of Medical Genetics and Applied Genomics, Radiation Physics, School of Life Science, Department of Basic Biology, The Graduate University for Advanced Studies, CIBER de Enfermedades Neurodegenerativas (CIBERNED), Doshisha University, National Cancer Research Center [Tokyo, Japan], University of Washington [Seattle], Department of Experimental Neurodegeneration [Göttingen, Germany], University Medical Center Göttingen (UMG), Cibles moléculaires et thérapeutiques de la maladie d'Alzheimer (CIMoTHeMA), Université de Poitiers, Laboratoire de Probabilités et Modèles Aléatoires (LPMA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), BioCeV-Institute of Microbiology, Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique (MEPPOT - U1147), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Istituto di chimica biologica, Università degli Studi di Verona, Département Image et Traitement Information (ITI), Institut Mines-Télécom [Paris] (IMT)-Université européenne de Bretagne - European University of Brittany (UEB)-Télécom Bretagne, Department of Cell Biology and Biophysics, Università degli Studi di Firenze [Firenze], Cell Immunity in Cancer, Inflammation and infection Group [Zaragoza, Spain] (Biomedical Research Center), Nanoscience Institute of Aragon - INA [Zaragoza, Spain]-Fundación Agencia Aragonesa para la Investigación y el Desarrollo - ARAID [Zaragoza, Spain]-University of Zaragoza - Universidad de Zaragoza [Zaragoza], Department of Pediatrics, Università degli studi di Napoli Federico II, Transfert de Genes a Visee Therapeutique Dans les Cellules Souches, Developpement Normal et Pathologique du Système Immunitaire, Signalisation et physiopathologie des cellules épithéliales, Facultad de Medicina, Universidad de Santiago de Chile [Santiago] (USACH), Departamento de Farmacobiología, Cinvestav-Sede Sur, Centre de recherche Croissance et signalisation (UMR_S 845), College of Life Sciences, Central China Normal University, Institute of Molecular Biotechnology, Austrian Academy of Sciences (OeAW), Laboratory of Cardiac Surgical Research, Monash University [Clayton], Universidade do Minho, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Neurodegenerative Diseases Research Group (CIBERNED), Vall d'Hebron Research Institute-Center for Networked Biomedical Research on Neurodegenerative Diseases, Barcelona, Department of medicine, Syracuse, NY, USA, State University of New York (SUNY), National University of Singapore (NUS)-Yong Loo Lin School of Medicine-Graduate School for Integrative Sciences and Engineering, McGill University Health Center [Montreal] (MUHC), National Institute for Infectious Diseases, Transporteurs en Imagerie et Radiothérapie en Oncologie (TIRO - UMR E4320), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-UMR E4320 (TIRO-MATOs), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Nice Sophia Antipolis (... - 2019) (UNS), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Biomedical Sciences, Department of Genetics of Eukaryotic Microorganisms, Georg-August-University [Göttingen]-Institute of Microbiology and Genetics, Sterol metabolism and therapeutic innovations in oncology, Institut Claudius Regaud, CRLCC Institut Claudius Regaud-CRLCC Institut Claudius Regaud-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Department of Molecular, Cellular and Developmental Biology, Señalización Celular 4, Institute of integrative biology (Liverpool), University of Liverpool, Department of Human Biology, University of Cape Town, National Institute of Diabetes and Digestive and Kidney Diseases [Bethesda], Department of Molecular Biology, Eberhard Karls Universität Tübingen, Technical University of Munich (TUM), Biophysics and Bioinformatics Laboratory, Department of Cell Biology and Morphology, Université de Lausanne (UNIL), Shenyang Institute of Automation, the Chinese Academy of Sciences (SIA), Key Laboratory of Thermo-Fluid Science and Engineering of Ministry of Education, Xi'an Jiaotong University (Xjtu), Dipartimento di Biologia, Mechanics laboratory , UniversityAmar Telidji, 3000 Laghouat, Algéria., Mechanics laboratory , University Amar Telidji, sans affiliation, Service d'hépatologie [Hôpital Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), University of Waterloo, Waterloo, ON, Canada, Institute of Cell Biology and Immunology, University of Stuttgart, Chaperones Research Group, Institute of Biosciences and Technology [Houston, TX, États-Unis] (IBT), Texas A&M Health Science Center [Houston, TX, États-Unis] (TAMHSC), Texas A&M University Health Science Center-Texas A&M University Health Science Center, Aquatic and Crop Resource Development, National Research Council of Canada (NRC), Cibles thérapeutiques, formulation et expertise pré-clinique du médicament (CITHEFOR), Université de Lorraine (UL), Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche [Ancona] (UNIVPM), Department of Biochemistry and Molecular Biology [Indianapolis, IN, USA], Indiana University School of Medicine, Indiana University System-Indiana University System, Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, iMed.UL, Faculty of Pharmacy, University of Lisbon, CESAM & Biology Department, Universidade de Aveiro, Celullar and Molecular Medicine, Università degli Studi di Perugia (UNIPG), Institute of Clinical Molecular Biology, Kiel University, Apoptose et Système Immunitaire (ASI), Vieillissement Cellulaire Intégré et Inflammation (VCII), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Mathematical Sciences [Aalborg], Aalborg University [Denmark] (AAU), Cambridge Institute for Medical Research (CIMR), University of Cambridge [UK] (CAM), Biozentrum, University of Basel (Unibas), Structural and Computational Biology Unit, European Molecular Biology Laboratory [Grenoble] (EMBL), Rutgers New Jersey Medical School (NJMS), Rutgers University System (Rutgers), Université de Perpignan Via Domitia (UPVD), Universidad Pablo de Olavide [Sevilla] (UPO), Department of Neurosciences, Agronomes et Vétérinaires Sans Frontières (AVSF), AVSF, Department of Mathematics [Gakushuin], Gakushuin University, Department of Internal Medicine [Münster, Germany], University of Münster, Neurogenetics laboratory, University Medicine Goettingen, Institut de biologie structurale (IBS - UMR 5075), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), Université d'Uruguay, Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Institute for Conservation & Improvement of Valentian Agrodiversity (COMAV), Universitat Politecnica de Valencia (UPV), ICBM, University of Chile [Santiago]-Faculty of Medicine, Nutrition, Métabolisme, Aquaculture (NuMéA), Institut National de la Recherche Agronomique (INRA)-Université de Pau et des Pays de l'Adour (UPPA), Department of Cell Biology, Baltimore, Johns Hopkins University School of Medicine, Baylor College of Medicine (BCM), Baylor University, University of Minnesota Medical School, Beijing Candid soft Technology Co. Ltd, Nanjing University of Information Science and Technology, Department of Hepatobiliary and Pancreatic Surgery [Maebashi, Japan], Gunma University Graduate Schoolof Medicine [Maebashi, Japan], Department of Molecular Genetics [Maastricht, The Netherlands], Maastricht University [The Netherlands], Institute of Cell Biology and Genetic Engineering, National Academy of Sciences of Ukraine (NASU), Institute of Pharmacology of Natural Products and Clinical Pharmacology, Institute of Pharmacology, University of Bern, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Wilmer Eye Institute, Mayo Clinic and Mayo College of Medicine, Rochester, Institute of Biochemistry and Biophysics, Polska Akademia Nauk (PAN)-Sciences, Department of Electrical and Computer Engineering [Waterloo] (ECE), University of Waterloo [Waterloo], Department of Chemistry and Toxicology, Norwegian Veterinary Institute, Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center [Houston], University of Minho, Friedrich Miescher Laboratory (FML), Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Department of Biomedical Sciences and Biotechnologies, Brescia University, Department of Physiological Chemistry [Bochum], Ruhr-Universität Bochum [Bochum], University of Oslo (UiO), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Facultés Universitaires Notre Dame de la Paix (FUNDP), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), École pratique des hautes études (EPHE)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226, Université du Québec à Montréal = University of Québec in Montréal (UQAM), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Université Lille 2 - Faculté de Médecine -Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Université de Franche-Comté (UFC), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon), Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Toulouse 1 Capitole (UT1)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse 1 Capitole (UT1)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées, Université libre de Bruxelles (ULB), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Universidade Federal do Rio de Janeiro (UFRJ), Institut Bergonié [Bordeaux], UNICANCER, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Trafic membranaire et Division cellulaire - Membrane Traffic and Cell Division, Centre National de la Recherche Scientifique (CNRS)-CentraleSupélec-Université Paris-Sud - Paris 11 (UP11), McGill University = Université McGill [Montréal, Canada], Service d'Anatomie et Cytologie Pathologique [CHU Rouen], Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Signaling in Oncogenesis, Angiogenesis and Permeability (CRCINA-ÉQUIPE 15), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Universidad de Chile = University of Chile [Santiago] (UCHILE), Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III (ISC), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Université Panthéon-Sorbonne (UP1)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Collège de France (CdF (institution)), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Great Ormond Street Hospital for Children [London] (GOSH)-Institute of Child Health, Hokkaido University [Sapporo, Japan], Université Paris sciences et lettres (PSL), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université de Lyon-Université de Lyon, Centre d’Infection et d’Immunité de Lille (CIIL) - INSERM U1019 - UMR 9017 (CIIL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Organisation Nucléaire et Oncogenèse - Nuclear Organization and Oncogenesis, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon], Centre National de la Recherche Scientifique (CNRS)-Institut de biologie physico-chimique (IBPC (FR_550)), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU), The Beatson Institute for Cancer Research, Beijing Normal University (BNU), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Fédération de Recherche Bézout-ESIEE Paris-École des Ponts ParisTech (ENPC)-Université Paris-Est Marne-la-Vallée (UPEM), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA), Université de Lyon-Université de Lyon-Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon], Vall d’Hebron Research Institute (VHIR), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Universidade Nova de Lisboa = NOVA University of Lisboa (NOVA), Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Doshisha University [Kyoto], Université européenne de Bretagne - European University of Brittany (UEB)-Télécom Bretagne-Institut Mines-Télécom [Paris] (IMT), Università degli Studi di Firenze = University of Florence [Firenze], University of Zaragoza - Universidad de Zaragoza [Zaragoza]-Nanoscience Institute of Aragon - INA [Zaragoza, Spain]-Fundación Agencia Aragonesa para la Investigación y el Desarrollo - ARAID [Zaragoza, Spain], Central China Normal University [Wuhan, China], Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-UMR E4320 (TIRO-MATOs), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut Claudius Regaud, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de biologie structurale [1992-2019] (IBS - UMR 5075 [1992-2019]), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Nanjing University of Information Science and Technology (NUIST), Facultad de Medicina [Buenos Aires], Universidad de Buenos Aires [Buenos Aires] (UBA)-Universidad de Buenos Aires [Buenos Aires] (UBA)-Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Clermont Auvergne (UCA)-Institut National de la Recherche Agronomique (INRA), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET)-Universidad Nacional de San Martin (UNSAM), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, George Mason University [Fairfax]-Center for Applied Proteomics and Molecular Medicine, Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Institute of Infection, Immunity and Inflammation [Glasgow, UK]-University of Glasgow, Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Settore BIO/06, biology, Cell Biology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, biology.organism_classification, Cell biology, Interpretation (model theory), 03 medical and health sciences, Arama, 030104 developmental biology, Molecular Biology, Humanities, ComputingMilieux_MISCELLANEOUS
Abstract: Author(s): Klionsky, DJ; Abdelmohsen, K; Abe, A; Abedin, MJ; Abeliovich, H; Arozena, AA; Adachi, H; Adams, CM; Adams, PD; Adeli, K; Adhihetty, PJ; Adler, SG; Agam, G; Agarwal, R; Aghi, MK; Agnello, M; Agostinis, P; Aguilar, PV; Aguirre-Ghiso, J; Airoldi, EM; Ait-Si-Ali, S; Akematsu, T; Akporiaye, ET; Al-Rubeai, M; Albaiceta, GM; Albanese, C; Albani, D; Albert, ML; Aldudo, J; Algul, H; Alirezaei, M; Alloza, I; Almasan, A; Almonte-Beceril, M; Alnemri, ES; Alonso, C; Altan-Bonnet, N; Altieri, DC; Alvarez, S; Alvarez-Erviti, L; Alves, S; Amadoro, G; Amano, A; Amantini, C; Ambrosio, S; Amelio, I; Amer, AO; Amessou, M; Amon, A; An, Z; Anania, FA; Andersen, SU; Andley, UP; Andreadi, CK; Andrieu-Abadie, N; Anel, A; Ann, DK; Anoopkumar-Dukie, S; Antonioli, M; Aoki, H; Apostolova, N; Aquila, S; Aquilano, K; Araki, K; Arama, E; Aranda, A; Araya, J; Arcaro, A; Arias, E; Arimoto, H; Ariosa, AR; Armstrong, JL; Arnould, T; Arsov, I; Asanuma, K; Askanas, V; Asselin, E; Atarashi, R; Atherton, SS; Atkin, JD; Attardi, LD; Auberger, P; Auburger, G; Aurelian, L; Autelli, R
Published: 2016

22. Protein biomarkers discriminate Leishmania major-infected and non-infected individuals in areas endemic for cutaneous leishmaniasis

Author: Amel Meddeb-Garnaoui, Valentina Libri, Matthew L. Albert, Ikbel Naouar, Darragh Duffy, Hechmi Louzir, Wafa Kammoun-Rebai, Université de Tunis El Manar (UTM), Laboratoire de Parasitologie Médicale, Biotechnologies et Biomolécules (LR11IPT06), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Laboratoire de Transmission, Contrôle et Immunobiologie des Infections - Laboratory of Transmission, Control and Immunobiology of Infection (LR11IPT02), Centre d'Immunologie Humaine (CIH), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunobiologie des Cellules dendritiques, This work was supported by the NIH/NIAID Grant no. SP50AI074178 and the Institut Pasteur International Network (RIIP), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Pasteur Tunis, Institut
Subjects: Male, 0301 basic medicine, Chemokine, medicine.medical_treatment, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Leishmania major, Child, Leishmaniasis, Immunoassay, Principal Component Analysis, Interleukin-13, biology, Interleukin-17, Asymptomatic infection, 3. Good health, Infectious Diseases, Cytokine, Protein biomarkers, Interleukin 13, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Cytokines, Female, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Research Article, Adolescent, 030231 tropical medicine, Leishmaniasis, Cutaneous, Antigens, Protozoan, Sensitivity and Specificity, 03 medical and health sciences, Immune system, Cutaneous leishmaniasis, medicine, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, Skin Tests, Innate immune system, biology.organism_classification, medicine.disease, Virology, Cross-Sectional Studies, 030104 developmental biology, Immunology, Leukocytes, Mononuclear, biology.protein, Biomarkers
Abstract: Background A successful host immune response to infection is dependent upon both innate and adaptive immune effector mechanisms. Cutaneous leishmaniasis results in an adaptive Th1 CD4+ T cell response that efficiently clears the parasite, but may also result in scaring. However the role of innate mechanisms during parasite clearance remains less well defined. Methods We examined a unique cohort of individuals, living in a Leishmania major endemic region, that were stratified among 3 distinct clinical groups in a cross-sectional study. Specifically, patients were classified either as healed (n = 17), asymptomatic (23), or naïve to infection (18) based upon the classical Leishmanin Skin Test (LST) and the presence or absence of scars. Utilizing a multiplexed immunoassay approach we characterized the induced cytokine and chemokine response to L. major. Results A subset of innate immune molecules was induced in all groups. By contrast, T cell-associated cytokines were largely induced in exposed groups as compared to L. major-infection naïve individuals. Two exceptions were IL-17A and IL-12p70, induced and not induced, respectively, in naïve individuals. In addition, GM-CSF was more strongly induced in healed patients as compared to the other two groups. Surprisingly an IL-13 response was the best cytokine for classifying previously infected donors. Conclusions Exploratory data analysis, utilizing principle component analysis (PCA), revealed distinct patient clusters of the healed and naïve groups based on the most differentially induced proteins. Asymptomatic previously infected individuals were more difficult to assign to a particular cluster based on these induced proteins. Analysis of these proteins may enable the identification of biomarkers associated with disease, leading to a better understanding of the protective mechanisms of immune response against leishmaniasis. Electronic supplementary material The online version of this article (doi:10.1186/s12879-016-1458-6) contains supplementary material, which is available to authorized users.
Published: 2016

23. In vivo imaging of inflammasome activation reveals a subcapsular macrophage burst response that mobilizes innate and adaptive immunity

Author: Béatrice Breart, Matthew L. Albert, Fabrice Lemaître, David Michonneau, Philippe Bousso, Zacarias Garcia, Pervinder Sagoo, Yves Levy, Dynamiques des Réponses Immunes, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), Immunobiologie des Cellules Dendritiques, Institut de Recherche sur le Vaccin (VRI), PRES Université Paris-Est-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'immunologie clinique [Créteil], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), This work was supported by Institut Pasteur (P.B.), Institut National de la Santé et de la Recherche Médicale (P.B.), the Vaccine Research Institute (P.B.), Fondation pour la Recherche Médicale (P.B.) and a Starting Grant from the European Research Council (P.B.)., European Project: 260499,EC:FP7:ERC,ERC-2010-StG_20091118,LYMPHOCYTECONTACTS(2011), and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Inflammasomes, viruses, T-Lymphocytes, T cell, [SDV]Life Sciences [q-bio], Vaccinia virus, Poxviridae Infections, Adaptive Immunity, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, AIM2, Immune system, Immunity, medicine, Animals, Macrophage, Toll-like receptor, Macrophages, Inflammasome, General Medicine, Flow Cytometry, Acquired immune system, Immunity, Innate, 3. Good health, Cell biology, CARD Signaling Adaptor Proteins, 030104 developmental biology, medicine.anatomical_structure, Immunology, Lymph Nodes, Apoptosis Regulatory Proteins, medicine.drug
Abstract: International audience; The inflammasome is activated in response to a variety of pathogens and has an important role in shaping adaptive immunity, yet the spatiotemporal orchestration of inflammasome activation in vivo and the mechanisms by which it promotes an effective immune response are not fully understood. Using an in vivo reporter to visualize inflammasome assembly, we establish the distribution, kinetics and propagation of the inflammasome response to a local viral infection. We show that modified vaccinia Ankara virus induces inflammasome activation in subcapsular sinus (SCS) macrophages, which is immediately followed by cell death and release of extracellular ASC specks. This transient inflammasome signaling in the lymph node generates a robust influx of inflammatory cells and mobilizes T cells from the circulation to increase the magnitude of T cell responses. We propose that after infection, SCS macrophages deliver a burst response of inflammasome activity and cell death that translates into the broadening of T cell responses, identifying an important aspect of inflammasome-driven vaccination strategies.
Published: 2015

24. Bystander hyperactivation of preimmune CD8+ T cells in chronic HCV patients

Author: Tobias Flecken, Jeremy Boussier, Farhad Heshmati, Vincent Mallet, Marit M. van Buuren, Francesco Nicoli, Matthew L. Albert, Aurélie Schnuriger, Ton N. Schumacher, Philippe Sultanik, Laurence Bousquet, Elisabetta Bianchi, Robert Thimme, Annick Lim, A. Garbarg-Chenon, Darragh Duffy, Antoine Toubert, Kerstin Johnsson, Emmanuel Clave, Stanislas Pol, Estelle Mottez, Cécile Alanio, Brieuc Perot, Victor Appay, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Immunologie Humaine (CIH), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Albert-Ludwigs-Universität Freiburg, Immunorégulation, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Département d'Immunologie - Department of Immunology, Institut Pasteur [Paris], Hôpital Saint-Louis, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Lund University [Lund], Université Paris Descartes - Paris 5 (UPD5), EFS [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre d'Immunologie Humaine ( CIH ), Centre d'Immunologie et de Maladies Infectieuses ( CIMI ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Département d'Immunologie, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ), Netherlands Cancer Institute ( NKI ), Laboratoire de virologie [CHU Trousseau], Université Paris Descartes - Paris 5 ( UPD5 ), CHU Cochin [AP-HP], and HAL UPMC, Gestionnaire
Subjects: chronic inflammation, medicine, Hepacivirus, CD8-Positive T-Lymphocytes, Lymphocyte Activation, TCR signaling, immunology, 0302 clinical medicine, CD8 T cell dysfunction, Receptors, Cytotoxic T cell, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Pre-immune repertoire, Biology (General), Chronic, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, General Neuroscience, human biology, General Medicine, Hepatitis C, 3. Good health, medicine.anatomical_structure, Antigen, [SDV.IMM]Life Sciences [q-bio]/Immunology, Research Article, Signal Transduction, [SDV.IMM] Life Sciences [q-bio]/Immunology, Naive T cell, viral immunology, QH301-705.5, T cell, Science, Receptors, Antigen, T-Cell, Biology, CD5 Antigens, General Biochemistry, Genetics and Molecular Biology, NO, 03 medical and health sciences, Immune system, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, human, Cross-Sectional Studies, Hepatitis C, Chronic, Humans, Human Biology and Medicine, 030304 developmental biology, General Immunology and Microbiology, T-cell receptor, T-Cell, Chronic infection, Immunology, CD5, CD8, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology
Abstract: Chronic infection perturbs immune homeostasis. While prior studies have reported dysregulation of effector and memory cells, little is known about the effects on naïve T cell populations. We performed a cross-sectional study of chronic hepatitis C (cHCV) patients using tetramer-associated magnetic enrichment to study antigen-specific inexperienced CD8+ T cells (i.e., tumor or unrelated virus-specific populations in tumor-free and sero-negative individuals). cHCV showed normal precursor frequencies, but increased proportions of memory-phenotype inexperienced cells, as compared to healthy donors or cured HCV patients. These observations could be explained by low surface expression of CD5, a negative regulator of TCR signaling. Accordingly, we demonstrated TCR hyperactivation and generation of potent CD8+ T cell responses from the altered T cell repertoire of cHCV patients. In sum, we provide the first evidence that naïve CD8+ T cells are dysregulated during cHCV infection, and establish a new mechanism of immune perturbation secondary to chronic infection. DOI: http://dx.doi.org/10.7554/eLife.07916.001, eLife digest Long-lasting or “chronic” infections massively perturb the immune system as a way to favor their own growth. In particular, they can stop T cells – a subtype of immune cells that help to destroy viruses – from working well. For example, HIV and hepatitis C viruses can overwork T cells and cause them to die. This can make individuals vulnerable to other infections. In healthy people, T cells that have participated in the fight against particular infections continue to live to provide a memory of those past infections. Groups of “naïve” T cells that have not yet encountered an infected cell also patrol the body, ready to respond to infections by a new virus. There are relatively few virus-specific naïve T cells in the body, so until recently it has been hard to study them. As a result, researchers know little about how these cells are affected by long-lasting infections, and whether chronic infection affects our capacity to fight unrelated infections. Alanio et al. have now used a highly sensitive technique to compare naïve T cells found in the blood of three groups of people: those with chronic hepatitis C infections, those who have been cured of a chronic hepatitis C infection, and healthy people. This revealed that the naïve T cells are negatively affected by chronic hepatitis C infections, and become hypersensitive: they get easily overexcited, which can lead to their death. This compromises the immune defenses at the moment they are most needed. Closer inspection showed that the naïve T cells of patients with hepatitis C are hypersensitive because they have less of a protein called CD5 on their surface. This protein acts as a natural brake for the T cells, and thus having less results in the T cells mounting stronger immune responses. Although this might be beneficial when fighting certain infections, this may also account for conditions where T cells attack healthy tissues. Finally, Alanio et al. found evidence that people who have been cured of a chronic hepatitis C infection recover a healthy set of naïve T cells within two years. Treating patients as soon as an infection is diagnosed therefore has several benefits: as well as clearing the virus, this will reset the immune system balance and reduce the damage that hyperactive immune cells cause to the body. The results also have implications for vaccinations, which work by pushing naïve T cells to arm themselves against a particular virus. The discovery that naïve T cells are hypersensitive in patients with hepatitis C suggests that we may need a distinct strategy for efficiently vaccinating these patients. It is indeed possible that standard vaccines – tested in groups of healthy people – may result in unexpected and unwanted immune responses in individuals with hepatitis C. These open questions will be addressed in further studies. It will also be of interest to know if other chronic viruses have the same ability to alter the activity of naïve T cells. DOI: http://dx.doi.org/10.7554/eLife.07916.002
Published: 2015

25. Inhibition of mTORC1 Enhances the Translation of Chikungunya Proteins via the Activation of the MnK/eIF4E Pathway

Author: Matthew L. Albert, Florence Guivel-Benhassine, Pierre-Emmanuel Joubert, Olivier Schwartz, Kenneth A. Stapleford, Marco Vignuzzi, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Populations virales et Pathogenèse - Viral Populations and Pathogenesis, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Virus et Immunité - Virus and immunity, Virus et Immunité, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Centre d'Immunologie Humaine (CIH), This work was supported by La Ligue Contre le Cancer and L’Agence Nationale de la Recherche. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Virus et Immunité - Virus and immunity (CNRS-UMR3569), and Ziani, Isma
Subjects: [SDV]Life Sciences [q-bio], Gene Knockout Techniques, Mice, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Protein biosynthesis, RNA, Small Interfering, lcsh:QH301-705.5, 0303 health sciences, TOR Serine-Threonine Kinases, EIF4E, virus diseases, Translation (biology), Flow Cytometry, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Chikungunya virus, Research Article, Signal Transduction, lcsh:Immunologic diseases. Allergy, Blotting, Western, Immunology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Mechanistic Target of Rapamycin Complex 1, Biology, Transfection, Microbiology, Host-Parasite Interactions, Viral Proteins, 03 medical and health sciences, Viral life cycle, Virology, Genetics, Animals, Gene silencing, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, PI3K/AKT/mTOR pathway, 030304 developmental biology, Blotting, Northern, Type I interferon production, Disease Models, Animal, Eukaryotic Initiation Factor-4E, lcsh:Biology (General), Viral replication, Multiprotein Complexes, Protein Biosynthesis, Chikungunya Fever, Parasitology, lcsh:RC581-607
Abstract: Chikungunya virus (CHIKV), the causative agent of a major epidemic spanning five continents, is a positive stranded mRNA virus that replicates using the cell’s cap-dependent translation machinery. Despite viral infection inhibiting mTOR, a metabolic sensor controls cap-dependent translation, viral proteins are efficiently translated. Rapalog treatment, silencing of mtor or raptor genes, but not rictor, further enhanced CHIKV infection in culture cells. Using biochemical assays and real time imaging, we demonstrate that this effect is independent of autophagy or type I interferon production. Providing in vivo evidence for the relevance of our findings, mice treated with mTORC1 inhibitors exhibited increased lethality and showed a higher sensitivity to CHIKV. A systematic evaluation of the viral life cycle indicated that inhibition of mTORC1 has a specific positive effect on viral proteins, enhancing viral replication by increasing the translation of both structural and nonstructural proteins. Molecular analysis defined a role for phosphatidylinositol-3 kinase (PI3K) and MAP kinase-activated protein kinase (MnKs) activation, leading to the hyper-phosphorylation of eIF4E. Finally, we demonstrated that in the context of CHIKV inhibition of mTORC1, viral replication is prioritized over host translation via a similar mechanism. Our study reveals an unexpected bypass pathway by which CHIKV protein translation overcomes viral induced mTORC1 inhibition., Author Summary The ongoing chikungunya epidemic outbreak in the Caribbean, Central and South America highlights how poor is our understanding of CHIKV pathogenesis and the urgent need for new strategies that may limit CHIKV spread. Immunological studies have suggested that dissemination of infection is largely determined by early events of viral-host cell interactions. In our prior study, we investigated the role of type I interferon responses and the autophagy pathway as mediators of viral control. Here, we evaluated the role of mTOR, making the surprising discovery that inhibition of mTORC1 enhances viral protein translation independently of type I IFN and autophagy. While the inhibition of mTORC1 has no impact on viral binding or entry, we observed an increased translation of both structural and nonstructural viral proteins. Interestingly, the positive impact of mTORC1 inhibition is restricted to viral proteins, as compared to host cap-dependent protein translation that remains suppressed. Further analysis demonstrates that this bypass pathway is mediated the activation of PI3K and MnKs, which in turn hyper-phosphorylate eIF4E, a critical initiation protein for translation. Notably, CHIKV replication enables this pathway as a means to efficiently replicate. Thus, our study provides an unexpected role for mTORC1 in the control of CHIKV infection and highlights a new strategy by which the expression of CHIKV proteins can bypass and/or use the inhibition of mTORC1.
Published: 2015

26. Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy

Author: Rosa Barreira da Silva, Melissa E Laird, Nader Yatim, Laurence Fiette, Molly A Ingersoll, Matthew L Albert, Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Histopathologie humaine et Modèles animaux, Institut Pasteur [Paris] (IP), Funding was provided by the Institut Pasteur (Pasteur-Roux post-doctoral fellowship to R.B.d.S.), the Pasteur Foundation (fellowship to M.E.L.), the Ligue Contre le Cancer (M.L.A.), the Fondation ARC pour la recherche sur le cancer (M.L.A.) and the French government's Invest in the Future Program, managed by the Agence Nationale de la Recherche (LabEx Immuno-Onco (R.B.d.S., M.E.L., N.Y., M.A.I. and M.L.A.))., ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris]
Subjects: Male, Adoptive cell transfer, Lymphocyte, medicine.medical_treatment, Cancer immunotherapy, MESH: Flow Cytometry, CXCR3, MESH: Mice, Knockout, MESH: Cell Movement/drug effects, 0302 clinical medicine, Cell Movement, MESH: Triazoles/pharmacology, Immunology and Allergy, MESH: Animals, MESH: Chemokines/metabolism, Lymphocytes, Mice, Knockout, Mice, Inbred BALB C, 0303 health sciences, Chemistry, Flow Cytometry, Adoptive Transfer, 3. Good health, MESH: Dipeptidyl Peptidase 4/immunology, medicine.anatomical_structure, MESH: Neoplasms, Experimental/genetics, MESH: Dipeptidyl Peptidase 4/genetics, MESH: Pyrazines/pharmacology, Pyrazines, 030220 oncology & carcinogenesis, MESH: Neoplasms, Experimental/immunology, MESH: Chemokine CXCL10/metabolism, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Immunotherapy, Chemokines, MESH: Chemokine CXCL10/immunology, Receptors, CXCR3, MESH: Cell Line, Tumor, MESH: Mice, Transgenic, Dipeptidyl Peptidase 4, T cell, Immunology, MESH: Mice, Inbred BALB C, MESH: Immunotherapy/methods, MESH: Cell Movement/immunology, Mice, Transgenic, MESH: Receptors, CXCR3/immunology, 03 medical and health sciences, Immune system, MESH: Mice, Inbred C57BL, Cell Line, Tumor, MESH: Lymphocytes/metabolism, medicine, Animals, CXCL10, MESH: Sitagliptin Phosphate, 030304 developmental biology, MESH: Neoplasms, Experimental/therapy, Dipeptidyl-Peptidase IV Inhibitors, Protein transport, MESH: Dipeptidyl-Peptidase IV Inhibitors/pharmacology, Sitagliptin Phosphate, Neoplasms, Experimental, Triazoles, MESH: Male, Chemokine CXCL10, Mice, Inbred C57BL, MESH: Adoptive Transfer, MESH: Receptors, CXCR3/metabolism, MESH: Dipeptidyl Peptidase 4/metabolism, MESH: Lymphocytes/immunology, MESH: Female, MESH: Chemokines/immunology
Abstract: International audience; The success of antitumor immune responses depends on the infiltration of solid tumors by effector T cells, a process guided by chemokines. Here we show that in vivo post-translational processing of chemokines by dipeptidylpeptidase 4 (DPP4, also known as CD26) limits lymphocyte migration to sites of inflammation and tumors. Inhibition of DPP4 enzymatic activity enhanced tumor rejection by preserving biologically active CXCL10 and increasing trafficking into the tumor by lymphocytes expressing the counter-receptor CXCR3. Furthermore, DPP4 inhibition improved adjuvant-based immunotherapy, adoptive T cell transfer and checkpoint blockade. These findings provide direct in vivo evidence for control of lymphocyte trafficking via CXCL10 cleavage and support the use of DPP4 inhibitors for stabilizing biologically active forms of chemokines as a strategy to enhance tumor immunotherapy.
Published: 2015

27. Dynamic Changes of Post-Translationally Modified Forms of CXCL10 and Soluble DPP4 in HCV Subjects Receiving Interferon-Free Therapy

Author: Darragh Duffy, Eric G. Meissner, Henry Masur, Shyam Kottilil, Matthew L. Albert, Jérémie Decalf, Armanda Casrouge, National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), Critical Care Medicine Department, National Institutes of Health - NIH, Division of Infectious Diseases, Department of Microbiology and Immunology, Medical University of South Carolina [Charleston] (MUSC), Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Human Virology (IHV), University of Maryland [Baltimore County] (UMBC), University of Maryland System-University of Maryland System, Centre d'Immunologie Humaine (CIH), This project was supported by federal funds from the intramural program of the National Institute of Allergy and Infectious Diseases, a PasteurInnov grant (Institut Pasteur), and the European Union FP7 grant PoC-HCV (GA n° 601851). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., European Project: 601851,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-2,POC-HCV(2013), Vougny, Marie-Christine, Point-of-care tests to revolutionise the clinical management of patients infected by Hepatitis C virus - POC-HCV - - EC:FP7:HEALTH2013-09-01 - 2016-08-31 - 601851 - VALID, and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, MESH: Hepacivirus/drug effects, Sofosbuvir, MESH: Fluorenes/therapeutic use, Hepacivirus, lcsh:Medicine, MESH: Hepatitis C, Chronic/virology, Blood plasma, medicine.disease_cause, Virus Replication, chemistry.chemical_compound, Recurrence, Viral replication, MESH: Interferons, Enzyme-linked immunoassays, MESH: Ribavirin/therapeutic use, lcsh:Science, MESH: Dipeptidyl Peptidase 4/blood, media_common, MESH: Treatment Outcome, Multidisciplinary, biology, Hepatitis C virus, Convalescence, virus diseases, MESH: Protein Processing, Post-Translational, Viral Load, MESH: Virus Replication/drug effects, 3. Good health, Treatment Outcome, MESH: Dipeptidyl Peptidase 4/genetics, [SDV.IMM]Life Sciences [q-bio]/Immunology, Drug Therapy, Combination, Female, Chemokines, Viral load, medicine.drug, Research Article, Ledipasvir, Adult, MESH: Sofosbuvir/therapeutic use, MESH: Hepatitis C, Chronic/drug therapy, [SDV.IMM] Life Sciences [q-bio]/Immunology, media_common.quotation_subject, Dipeptidyl Peptidase 4, MESH: Chemokine CXCL10/genetics, MESH: Convalescence, Antiviral Agents, MESH: Benzimidazoles/therapeutic use, MESH: Viral Load/drug effects, Ribavirin, MESH: Hepacivirus/physiology, medicine, Humans, Fluorenes, MESH: Humans, business.industry, lcsh:R, Correction, MESH: Adult, Hepatitis C, Chronic, MESH: Chemokine CXCL10/blood, biology.organism_classification, Statistical data, digestive system diseases, MESH: Male, Post translational modifications, MESH: Recurrence, Chemokine CXCL10, Regimen, MESH: Drug Therapy, Combination, chemistry, MESH: Hepatitis C, Chronic/blood, Immunology, MESH: Antiviral Agents/therapeutic use, lcsh:Q, Benzimidazoles, Interferons, business, Protein Processing, Post-Translational, MESH: Female, Biomarkers, MESH: Hepatitis C, Chronic/genetics
Abstract: Serum levels of the interferon (IFN)-stimulated chemokine CXCL10 are increased during chronic HCV infection and associate with outcome of IFN-based therapy. Elevated levels of NH2-terminal truncated CXCL10 (3-77aa), produced by DPP4 cleavage, negatively associate with spontaneous clearance of acute HCV infection and sustained virological response (SVR) with IFN-based therapy for chronic infection. The association of different CXCL10 forms and DPP4 with outcome during IFN-free HCV therapy has not been examined. Using novel Simoa assays, plasma was analyzed from HCV genotype-1 (GT1) subjects who relapsed (n = 11) or achieved SVR (n = 10) after sofosbuvir and ribavirin (SOF/RBV) treatment, and from SOF/RBV relapsers who achieved SVR with a subsequent SOF/ledipasvir regimen (n = 9). While the NH2-truncated form of CXCL10 was elevated in HCV infection relative to healthy controls, pre-treatment plasma concentrations of CXCL10 forms failed to stratify subjects based on treatment outcome to IFN-free regimens. However, a trend (statistically non-significant) towards elevated higher levels of total and long CXCL10 was observed pre-treatment in subjects who relapsed. All forms of CXCL10 decreased rapidly following treatment initiation and were again elevated in subjects who experienced HCV relapse, indicating that CXCL10 production may be associated with active viral replication. While soluble DPP4 (sDPP4) and NH2-truncated CXCL10 concentrations were highly correlated, on-treatment sDPP4 levels and activity declined more slowly than CXCL10, suggesting differential regulation. Conclusion These data suggest post-translationally modified forms of CXCL10 will not support the prediction of treatment outcome in HCV GT1 subjects treated with SOF/RBV.
Published: 2015

28. Baseline sensitivity of T cells to alpha-IFN correlates with sustained virological response to IFN-based triple therapy in HCV infection

Author: Christophe Hézode, Cécile Alanio, G. Uze, Armanda Casrouge, Vincent Mallet, I. Rosa-Hézode, P. Pellet, Estelle Mottez, Matthew L. Albert, Philippe Renard, Stanislas Pol, Philippe Sultanik, Laurence Bousquet, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Immunologie Humaine (CIH), Service d'hépato-gastro-entérologie [APHP Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Hospitalier Victor Dupouy, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), Service d'hépatologie médicale [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by grants from the Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS 11416) and ERC Starting award (M.A.). We thank the Fondation pour la Recherche Médicale for master and PhD student bursaries, We thank the Fondation pour la Recherche Médicale for master and PhD student bursaries, the Etablissement Français du Sang (EFS) for healthy donors samples, S. Pellegrini for critical review, S. Feton and K. Sperber for coordination of the clinical protocol, J. Gaston, S. Lagaye and M. Andrieu for technical assistance. We would also like to acknowledge the Department of Development, Reproduction and Cancer, Institut Cochin, Paris, the Department of Immunology, Institut Cochin, Paris, and the Centre d'Immunologie Humaine (CIH), Institut Pasteur, Paris, for support and technical expertise, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Pitié-Salpêtrière [APHP], CHU Cochin [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut Cochin (UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] - Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Henri Mondor - Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Montpellier 1 (UM1) - Université Montpellier 2 - Sciences et Techniques (UM2) - Université de Montpellier (UM) - Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Cochin [AP-HP]
Subjects: Male, MESH: T-Lymphocytes/metabolism, T-Lymphocytes, Drug Resistance, MESH: Hepatitis C, Chronic/virology, MESH: Leukocytes, Mononuclear/drug effects, Telaprevir, chemistry.chemical_compound, Pegylated interferon, Phosphorylation, MESH: Treatment Outcome, MESH: Aged, MESH: STAT1 Transcription Factor/metabolism, MESH: Middle Aged, biology, MESH: Polymorphism, Single Nucleotide, IFNα desensitization, IFN-based triple therapy, MESH: T-Lymphocytes/immunology, Middle Aged, Viral Load, MESH: Antiviral Agents/pharmacology, MESH: Interleukins/genetics, MESH: Case-Control Studies, 3. Good health, STAT1 Transcription Factor, Treatment Outcome, Infectious Diseases, MESH: Interferon-alpha/therapeutic use, [SDV.IMM]Life Sciences [q-bio]/Immunology, Drug Therapy, Combination, Female, MESH: Viral Load, medicine.drug, MESH: Leukocytes, Mononuclear/metabolism, MESH: Hepatitis C, Chronic/drug therapy, [SDV.IMM] Life Sciences [q-bio]/Immunology, CD3, MESH: T-Lymphocytes/drug effects, T cells, Alpha interferon, Antiviral Agents, Polymorphism, Single Nucleotide, Peripheral blood mononuclear cell, Virology, Boceprevir, medicine, Humans, Aged, MESH: Hepatitis C, Chronic/immunology, MESH: Humans, Hepatology, MESH: Phosphorylation, business.industry, Interleukins, Ribavirin, MESH: Drug Resistance/genetics, Interferon-alpha, Hepatitis C, Chronic, MESH: Male, MESH: Drug Therapy, Combination, MESH: Interferon-alpha/pharmacology, chemistry, MESH: Leukocytes, Mononuclear/immunology, Case-Control Studies, Immunology, MESH: Antiviral Agents/therapeutic use, Leukocytes, Mononuclear, biology.protein, chronic HCV infection, Interferons, business, MESH: Female, Ex vivo, MESH: Hepatitis C, Chronic/genetics
Abstract: International audience; Chronic infection with HCV is a public health problem with approximately 170 million people infected worldwide. Interferon alpha (IFNα) sensitivity in liver and IL28B genotype has been identified as important determinants of HCV clearance in the setting of pegylated interferon/ribavirin treatment. Herein, we explored IFNα sensitivity in PBMC from 21 healthy donors and 21 HCV-infected patients treated with pegylated interferon/ribavirin and HCV nonstructural protein-3 inhibitors (i.e. telaprevir/boceprevir). We explored phospho-STAT1 level as read-out for IFN signalling pathway activation in PBMC, T cells and monocytes and correlated results with virological response. We found that PBMC from healthy donors are desensitized to IFNα after priming and challenged with IFNα, with a subsequent decrease of phospho-STAT1 and interferon-stimulated genes. Furthermore, we show that CD3+ T cells, but not monocytes, become desensitized after 4 weeks of treatment, with a significant decrease of phospho-STAT1 after ex vivo IFNα stimulation. Finally, we identified baseline phospho-STAT1 level in CD3+ T cells as a potential biomarker of sustained virological response, regardless of the IL28B genotype. In the upcoming costly era of IFN-sparing regimen, baseline IFNα sensitivity could act as biomarker to define cost-effectiveness strategies of treatment by identifying patients who will or will not respond to IFN-based treatments.
Published: 2015

29. Harnessing the Host Immune Response to Infection – BCG Immunotherapy for Bladder Cancer

Author: Matthew L. Albert, Hana Zdimerova, Molly A. Ingersoll, Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), M. R. Shurin, Y. Thanavala, N. Ismail, and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Tuberculosis, Neutrophils, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Mycobacterium bovis, 030219 obstetrics & reproductive medicine, Bladder cancer, biology, business.industry, Immunotherapy, medicine.disease, Acquired immune system, biology.organism_classification, 3. Good health, Vaccination, Clinical trial, 030220 oncology & carcinogenesis, Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Bacillus Calmette–Guérin, business
Abstract: International audience; Bacillus Calmette–Guérin, or BCG, an avirulent strain of Mycobacterium bovis, was developed as a vaccine for the prevention of tuberculosis. BCG’s success in disease prevention resulted in the vaccination of billions of individuals. The observation that bacterial components could induce tumor regression, coupled with reports that BCG-vaccinated individuals demonstrated reduced cancer incidence, led to the development of BCG as an immunotherapeutic agent. The pioneering work of Morales and colleagues in the 1970s, demonstrating that direct instillation of live BCG into the bladder of patients with nonmuscle invasive bladder cancer prevented tumor recurrence, laid the path for what is arguably the most successful immunotherapy to date. Notably, although much work has focused on how BCG mediates tumor immunity, important unknowns regarding the mechanism of action remain. Nonspecific innate pathways, such as neutrophil-mediated killing, and adaptive immunity, such as induction of BCG- and tumor-specific T cells, likely work in concert to exert anti-tumor effects. Finally, as the mechanisms of action are unraveled, questions of pharmaco-equivalency of BCG substrains have arisen with respect to the clinical management of bladder cancer patients. Thus, while BCG immunotherapy is currently the standard of care for nonmuscle invasive bladder cancer, there exists great opportunity to improve upon this treatment through additional research and clinical trials.
Published: 2015

30. Apolipoprotein H expression is associated with IL28B genotype and viral clearance in hepatitis C virus infection

Author: Vincent Mallet, Christophe Hézode, Rasha Mamdouh, Mona Rafik, Alexandre Soulier, Isabelle Rosa, Amira Mohsen, Mai El-Daly, Lenaig Le-Fouler, Philippe Renard, Jacques Izopet, Philippe Bonnard, Melissa E. Laird, Armanda Casrouge, Arnaud Fontanet, Stanislas Pol, Mostafa K. Mohamed, Darragh Duffy, Jean-Michel Pawlotsky, Matthew L. Albert, Mohamed Abdel-Hamid, Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Community Medicine Department, National Research Center, Faculty of medicine, Université Ain Shams, Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), liver diseases research unit, National Hepatology & Tropical Medicine Research Institute, Minia University, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CNR for Viral Hepatitis B, C, and D, Hôpital Henri Mondor, Service d'hépato-gastro-entérologie [APHP Henri Mondor], Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Hôpital Henri Mondor-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of gastroenterology and hepatology, Hôpital Victor Dupouy, Service des maladies infectieuses et tropicales [CHU Tenon], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Virologie, CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Service d'hépatologie médicale [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by ANRS grants 12210, 12199, 12135 (MLA, AF), the European Research Council Young Investigator Award (MLA), and the European FP7 project SPHINX (ID 261365). Chronic HCV patient samples were provided from an Inserm sponsored clinical trial and also from the control arm of the REALIZE trial as run by Tibotec (Trial N° VX-950-TiDP24-C216). HCV/HIV patient samples were provided as part of the ANRS HC 20 ETOC study (NCT00901524)., European Project: 261365,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,SPHINX(2010), Epidémiologie des Maladies Emergentes, Pasteur-Cnam risques infectieux et émergents (PACRI), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], CHU Cochin [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire Virologie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
Subjects: Male, Very low-density lipoprotein, MESH: Ribavirin/administration & dosage, Apolipoprotein B, MESH: HIV Infections*/complications, IL28B, HIV Infections, Hepacivirus, Virus Replication, medicine.disease_cause, Polyethylene Glycols, chemistry.chemical_compound, MESH: Hepacivirus*/drug effects, Host factor, MESH: Treatment Outcome, MESH: Aged, MESH: Middle Aged, biology, Coinfection, Hepatitis C virus, MESH: Polymorphism, Single Nucleotide, Middle Aged, Viral Load, MESH: Hepatitis C*/complications Hepatitis, MESH: Virus Replication/drug effects, Hepatitis C, 3. Good health, Treatment Outcome, beta 2-Glycoprotein I, MESH: Interferon-alpha/administration & dosage, MESH: beta 2-Glycoprotein I*/blood, MESH: Antiviral Agents/administration & dosage, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH: Viral Load, Apolipoprotein H, Adult, Quantitative trait loci, MESH: C*/drug therapy Hepatitis, MESH: beta 2-Glycoprotein I*/genetic, Single-nucleotide polymorphism, Antiviral Agents, Polymorphism, Single Nucleotide, Ribavirin, MESH: Interleukins/genetics, medicine, Humans, SNP, Aged, MESH: C*/immunology Hepatitis, MESH: HIV Infections*/drug therapy, Hepatology, Interleukins, MESH: C*/physiopathology Humans, Interferon-alpha, MESH: Polyethylene Glycols/administration & dosage, MESH: Adult, Virology, MESH: Male, MESH: HIV Infections*/immunology, MESH: Coinfection, MESH: Hepacivirus*/physiology, Lipid metabolism, Apolipoproteins, chemistry, Immunology, biology.protein, MESH: C*/genetics Hepatitis, Interferons, MESH: Female
Abstract: International audience; BACKGROUND & AIMS:HCV requires host lipid metabolism for replication, and apolipoproteins have been implicated in the response to treatment.METHODS:We examined plasma apolipoprotein concentrations in three cohorts of patients: mono-infected patients with symptomatic acute hepatitis C (aHCV); those undergoing treatment for chronic hepatitis C (cHCV); and HIV/HCV co-infected patients being treated for their chronic hepatitis C. We also evaluated associations between apolipoproteins and IL28B polymorphisms, a defined genetic determinant of viral clearance.RESULTS:Plasma apolipoprotein H (ApoH) levels were significantly higher in patients who achieved spontaneous clearance or responded to pegylated-interferon/ribavirin therapy. Strikingly, patients carrying the IL28B rs12979860 CC SNP correlated with the plasma concentration of ApoH in all three cohorts. Both ApoH and IL28B CC SNP were associated with HCV clearance in univariate analysis. Additional multivariate analysis revealed that the association between IL28B and HCV clearance was closely linked to that of Apo H and HCV clearance, suggesting that both belong to the same biological pathway to clearance. The association between IL28B CC SNP and ApoH was not observed in healthy individuals, suggesting that early post-infection events trigger differential ApoH expression in an IL28B allele dependent manner.CONCLUSIONS:This relationship identifies ApoH as the first induced protein quantitative trait associated with IL28B, and characterises a novel host factor implicated in HCV clearance
Published: 2014

31. Functional analysis via standardized whole-blood stimulation systems defines the boundaries of a healthy immune response to complex stimuli

Author: Ivo Gomperts-Boneca, Ludovic Deriano, Spencer L. Shorte, Annick Dubois, Anavaj Sakuntabhai, Claude Leclerc, Caroline Demangel, Ana Cumano, Lluis Quintana-Murci, Matthew L. Albert, Antonio A. Freitas, Antoine Toubert, Lars Rogge, Manfred Schmolz, Gérard Eberl, Vincent Rouilly, Valentina Libri, Alejandra Urrutia, James P. Di Santo, Eric Tartour, Marie-Noëlle Ungeheuer, Françoise Dromer, Hugo Mouquet, Olivier Schwartz, Benoit Beitz, Mikael David, Olivier Lantz, Stéphanie Thomas, Ivo G. Boneca, Philippe Bousso, Laurent Abel, Vassili Soumelis, Cécile Delval, Darragh Duffy, Benno Schwikowski, Frédéric Tangy, Serge Hercberg, Jost Enninga, Milena Hasan, Samuel S.T. LaBrie, Sandra Pellegrini, Aurélie Bisiaux, Stanislas Pol, Marc Daëron, Andrés Alcover, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Centre d'Immunologie Humaine (CIH), Substances Lichéniques et Photoprotection, Université de Rennes (UR), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules Dendritiques, Myriad rules based medicine, Chambre Régionale d'Agriculture des Pays de la Loire, Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall (BGPB), Laboratoire de géographie physique : Environnements Quaternaires et Actuels (LGP), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Département d'Immunologie - Department of Immunology, Immunorégulation, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Génétique Evolutive Humaine - Human Evolutionary Genetics, Laboratory of Cellular Physiology and Immunology and Chris Browne Center, Rockefeller University [New York], St. Giles Laboratory of Human Genetics of Infectious Diseases, Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie Cellulaire des Lymphocytes - Lymphocyte Cell Biology, Dynamiques des Réponses Immunes, Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie de l'Infection - Immunobiology of Infection, Département de Génomes et Génétique - Department of Genomes and Genetics, Mycologie moléculaire, Centre National de Référence Mycologie et Antifongiques-Mycologie Moléculaire (CNRMA), Microenvironnement et Immunité - Microenvironment and Immunity, Dynamique des Interactions Hôte-Pathogène - Dynamics of Host-Pathogen Interactions, Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de formation en masso-kinésithérapie (IFMK Brest), Université de Brest (UBO)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Réponse humorale aux pathogènes, Signalisation des Cytokines - Cytokine Signaling, Service d'hépatologie médicale [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Centre de recherche sur les liens sociaux (CERLIS - UMR 8070), Université Sorbonne Nouvelle - Paris 3-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Biologie systémique - Systems Biology, Imagopole (CITECH), Laboratoire d'Immunologie Clinique, Institut Curie [Paris], Génomique virale et vaccination, Cytokines et Immunologie des Tumeurs Humaines (U753), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), This work benefited from support of the French government’s Invest in the Future Program, managed by the Agence Nationale de la Recherche (ANR, reference 10-LABX-69-01). We also acknowledge A. Pugsley for his support in obtaining funding and the logistical aspects of initiating the project, Milieu Intérieur Consortium (32 collaborateurs) : Abel L, Alcover A, Bousso P, Cumano A, Daëron M, Delval C, Demangel C, Deriano L, Di Santo J, Dromer F, Eberl G, Enninga J, Freitas A, Gomperts-Boneca I, Hercberg S, Lantz O, Leclerc C, Mouquet H, Pellegrini S, Pol S, Rogge L, Sakuntabhai A, Schwartz O, Schwikowski B, Shorte S, Soumelis V, Tangy F, Tartour E, Toubert A, Ungeheuer MN, Quintana-Murci L, Albert ML., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Paris 13 (UP13)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Université de Brest (UBO), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche Translationnelle ( CRT ), Centre d'Immunologie Humaine ( CIH ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ), Centre d'Immunologie et de Maladies Infectieuses ( CIMI ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Biologie et Génétique de la Paroi bactérienne, Laboratoire de géographie physique ( LGP ), Université Panthéon-Sorbonne ( UP1 ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Centre National de la Recherche Scientifique ( CNRS ), Département d'Immunologie, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), rockefeller university, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Biologie Cellulaire des Lymphocytes, Lymphopoïèse, Université Paris Diderot - Paris 7 ( UPD7 ) -PRES Sorbonne Paris Cité, Centre d'Immunologie de Marseille - Luminy ( CIML ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Immunobiologie de l'Infection, Département de Génomes et Génétique, Centre National de Référence Mycologie et Antifongiques-Mycologie Moléculaire ( CNRMA ), Microenvironnement et Immunité, Dynamique des Interactions Hôte-Pathogène, Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle ( CRESS - U1153 ), Université Paris 13 ( UP13 ) -Institut National de la Recherche Agronomique ( INRA ) -Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité ( CRESS (U1153 / UMR_A 1125) ), Institut National de la Recherche Agronomique ( INRA ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Recherche Agronomique ( INRA ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de formation en masso-kinésithérapie ( IFMK Brest ), Université de Brest ( UBO ) -Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Signalisation des Cytokines, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Génétique fonctionnelle des Maladies infectieuses, CERLIS - Centre de recherche sur les liens sociaux - UMR 8070 ( CERLIS - UMR 8070 ), Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Sorbonne Nouvelle - Paris 3, Biologie systémique, Imagopole ( CITECH ), Institut Curie, Institut Curie-Institut Curie, Cytokines et Immunologie des Tumeurs Humaines ( U753 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources ( ICAReB ), ANR : 10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE ( 2010 ), Centre de Recherche Translationnelle (CRT), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Université Panthéon-Sorbonne (UP1), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), CHU Cochin [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and ANR: 10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010)
Subjects: Chemokine, MESH : Cytokines, MESH : Antigens, Disease, MESH : Monitoring, Immunologic, Adaptive Immunity, 0302 clinical medicine, Immunophenotyping, Reference Values, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, MESH: Monitoring, Immunologic, MESH: Healthy Volunteers, 0303 health sciences, MESH: Cytokines, biology, MESH: Reference Values, MESH : Immunity, Innate, Healthy Volunteers, 3. Good health, MESH: Reproducibility of Results, Infectious Diseases, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Antigens, MESH: Immunity, Innate, Inflammation Mediators, Functional analysis (psychology), Whole blood stimulation, MESH : Adaptive Immunity, Immunology, MESH: Inflammation Mediators, MESH : Reference Values, MESH : Inflammation Mediators, 03 medical and health sciences, Immune system, Immunity, Monitoring, Immunologic, Humans, Antigens, 030304 developmental biology, MESH : Healthy Volunteers, MESH: Humans, MESH : Reproducibility of Results, MESH : Humans, Reproducibility of Results, Immunity, Innate, Reference values, biology.protein, MESH: Adaptive Immunity, 030215 immunology
Abstract: International audience; Standardization of immunophenotyping procedures has become a high priority. We have developed a suite of whole-blood, syringe-based assay systems that can be used to reproducibly assess induced innate or adaptive immune responses. By eliminating preanalytical errors associated with immune monitoring, we have defined the protein signatures induced by (1) medically relevant bacteria, fungi, and viruses; (2) agonists specific for defined host sensors; (3) clinically employed cytokines; and (4) activators of T cell immunity. Our results provide an initial assessment of healthy donor reference values for induced cytokines and chemokines and we report the failure to release interleukin-1α as a common immunological phenotype. The observed naturally occurring variation of the immune response may help to explain differential susceptibility to disease or response to therapeutic intervention. The implementation of a general solution for assessment of functional immune responses will help support harmonization of clinical studies and data sharing.
Published: 2014

32. Widespread mitochondrial depletion via mitophagy does not compromise necroptosis

Author: Matthew L. Albert, Stephen W.G. Tait, Nader Yatim, Maria Karvela, Douglas R. Green, Grahame J. Kidd, Sandra Milasta, Ruoning Wang, Stefan Krautwald, Andrew Oberst, Andreas Linkermann, Gabriel Ichim, Sharon Frase, Randall Wakefield, Giovanni Quarato, Martina Haller, CR-UK Beatson Institute, Institute of Cancer Sciences, University of Glasgow, University of Washington [Seattle], Department of immunology, St Jude Children's Research Hospital, Center for Childhood Cancer and Blood Disease, Ohio State University [Columbus] (OSU), Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Lerner Research Institute, Cleveland Clinic, Cell and Tissue Imaging Center, Division of Nephrology and Hypertension, Christian-Albrechts-Universität zu Kiel (CAU), This work was funded by the Royal Society and grants from the BBSRC (BB/K008374/1) (S.W.G.T.) grants AI44828 and CA169291 from the NIH (to D.R.G.), and the American Lebanese and Syrian Associated Charities. S.W.G.T. is a Royal Society University Research Fellow., Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lerner Research Institute [Cleveland, OH, USA], and Vougny, Marie-Christine
Subjects: Mitochondrial ROS, Programmed cell death, [SDV.IMM] Life Sciences [q-bio]/Immunology, Necroptosis, Mitochondrial Degradation, Butylated Hydroxyanisole, Apoptosis, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Mitochondrion, Mitochondrial depletion, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, Mice, Necrosis, 03 medical and health sciences, 0302 clinical medicine, Mitophagy, Animals, lcsh:QH301-705.5, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, Caspase 8, 0303 health sciences, Tumor Necrosis Factor-alpha, 3T3 Cells, Mitochondria, Cell biology, lcsh:Biology (General), Receptor-Interacting Protein Serine-Threonine Kinases, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Reactive Oxygen Species
Abstract: International audience; Programmed necrosis (or necroptosis) is a form of cell death triggered by the activation of receptor interacting protein kinase-3 (RIPK3). Several reports have implicated mitochondria and mitochondrial reactive oxygen species (ROS) generation as effectors of RIPK3-dependent cell death. Here, we directly test this idea by employing a method for the specific removal of mitochondria via mitophagy. Mitochondria-deficient cells were resistant to the mitochondrial pathway of apoptosis, but efficiently died via tumor necrosis factor (TNF)-induced, RIPK3-dependent programmed necrosis or as a result of direct oligomerization of RIPK3. Although the ROS scavenger butylated hydroxyanisole (BHA) delayed TNF-induced necroptosis, it had no effect on necroptosis induced by RIPK3 oligomerization. Furthermore, although TNF-induced ROS production was dependent on mitochondria, the inhibition of TNF-induced necroptosis by BHA was observed in mitochondria-depleted cells. Our data indicate that mitochondrial ROS production accompanies, but does not cause, RIPK3-dependent necroptotic cell death.
Published: 2013

33. Type I and Type III Interferons Drive Redundant Amplification Loops to Induce a Transcriptional Signature in Influenza-Infected Airway Epithelia

Author: Christophe Desmet, Matthew L. Albert, Peter Staeheli, Andreas Wack, Sophia Davidson, Matthew R. Buckwalter, Tanel Mahlakõiv, Stefania Crotta, National Institute for Medical Research (MRC), Department of Virology, University of Freiburg [Freiburg], Spemann Graduate School of Biology and Medicine (SGBM), Université de Liège, Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the UK Medical Research Council (SC, SD, AW) (U117597139), by the Deutsche Forschungsgemeinschaft (SFB 620) for PS and by a European Research Council Starting Award (MRB, MLA)., We are grateful to Dr. S. Akira and Dr. T. Taniguchi and for the permission to obtain organs from gene-deficient mice generated by them. The support from the MRC-NIMR facilities of Confocal Microscopy, Genomics and Biological Services is gratefully acknowledged., Vougny, Marie-Christine, and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Microarrays, MESH: Interferon Type I/metabolism, Interferon Regulatory Factor-7, MESH: Adaptor Proteins, Signal Transducing/metabolism, MESH: Orthomyxoviridae Infections/immunology, MESH: Epithelial Cells/immunology, medicine.disease_cause, MESH: Mice, Knockout, MESH: Respiratory Mucosa/pathology, Mice, 0302 clinical medicine, MESH: Adaptor Proteins, Signal Transducing/genetics, MESH: Interleukins/metabolism, MESH: Orthomyxoviridae Infections/metabolism, Influenza A virus, Viral replication, MESH: Influenza A virus/metabolism, MESH: Animals, Enzyme-linked immunoassays, MESH: Interferon Regulatory Factor-3/immunology, Receptor, lcsh:QH301-705.5, MESH: Interferon Regulatory Factor-7/immunology, Mice, Knockout, 0303 health sciences, MESH: Interferon Regulatory Factor-3/metabolism, MESH: Interferon Type I/genetics, virus diseases, MESH: Interleukins/genetics, MESH: Orthomyxoviridae Infections/genetics, 3. Good health, Cell biology, Genetic interference, Interferon Type I, MESH: Interferon Regulatory Factor-7/genetics, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Respiratory Mucosa/metabolism, Research Article, medicine.drug, MESH: Interferon Type I/immunology, lcsh:Immunologic diseases. Allergy, MESH: Epithelial Cells/metabolism, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Nerve Tissue Proteins, Receptors, Cell Surface, Respiratory Mucosa, Biology, Microbiology, Virus, MESH: Influenza A virus/immunology, 03 medical and health sciences, MESH: Membrane Proteins/genetics, Immune system, MESH: Interferon Regulatory Factor-3/genetics, Orthomyxoviridae Infections, MESH: Adaptor Proteins, Signal Transducing/immunology, Virology, Genetics, medicine, Animals, MESH: Membrane Proteins/metabolism, MESH: Influenza A virus/genetics, Molecular Biology, MESH: Mice, Adaptor Proteins, Signal Transducing, 030304 developmental biology, MESH: Epithelial Cells/virology, MESH: Nerve Tissue Proteins/metabolism, MESH: Epithelial Cells/pathology, Interleukins, MESH: Respiratory Mucosa/immunology, Membrane Proteins, Epithelial Cells, MESH: Membrane Proteins/immunology, MESH: Nerve Tissue Proteins/genetics, Influenza, MESH: Nerve Tissue Proteins/immunology, lcsh:Biology (General), MESH: Interferon Regulatory Factor-7/metabolism, MESH: Respiratory Mucosa/virology, IRF7, Interferon Regulatory Factor-3, Parasitology, Interferons, Gene expression, lcsh:RC581-607, IRF3, MESH: Interleukins/immunology, Interferon type I, 030215 immunology
Abstract: Interferons (IFNs) are a group of cytokines with a well-established antiviral function. They can be induced by viral infection, are secreted and bind to specific receptors on the same or neighbouring cells to activate the expression of hundreds of IFN stimulated genes (ISGs) with antiviral function. Type I IFN has been known for more than half a century. However, more recently, type III IFN (IFNλ, IL-28/29) was shown to play a similar role and to be particularly important at epithelial surfaces. Here we show that airway epithelia, the primary target of influenza A virus, produce both IFN I and III upon infection, and that induction of both depends on the RIG-I/MAVS pathway. While IRF3 is generally regarded as the transcription factor required for initiation of IFN transcription and the so-called “priming loop”, we find that IRF3 deficiency has little impact on IFN expression. In contrast, lack of IRF7 reduced IFN production significantly, and only IRF3−/−IRF7−/− double deficiency completely abolished it. The transcriptional response to influenza infection was largely dependent on IFNs, as it was reduced to a few upregulated genes in epithelia lacking receptors for both type I and III IFN (IFNAR1−/−IL-28Rα−/−). Wild-type epithelia and epithelia deficient in either the type I IFN receptor or the type III IFN receptor exhibit similar transcriptional profiles in response to virus, indicating that none of the induced genes depends selectively on only one IFN system. In chimeric mice, the lack of both IFN I and III signalling in the stromal compartment alone significantly increased the susceptibility to influenza infection. In conclusion, virus infection of airway epithelia induces, via a RIG-I/MAVS/IRF7 dependent pathway, both type I and III IFNs which drive two completely overlapping and redundant amplification loops to upregulate ISGs and protect from influenza infection., Author Summary The response of cells to virus infection depends on Interferons (IFNs), a group of cytokines which activate the expression of hundreds of genes that help control viral replication inside infected cells. While type I IFN was discovered in 1957, type III IFN (IFNλ, IL-28/29) was characterized recently and is known for its role in the response to hepatitis C virus. Airway epithelia are the primary target of influenza virus, and we studied how infection induces IFNs and which IFN is most important for the epithelial anti-influenza response. We found that infected epithelia detect virus through the cytoplasmic RIG-I/MAVS recognition system, leading to activation of the transcription factor IRF7 and subsequent induction of both type I and III IFNs. All ensuing cellular responses to infection are dependent on the production and secretion of IFNs, as responses are lost in epithelia lacking receptors for both type I and III IFNs. Finally, gene induction is indistinguishable in single receptor-deficient and wild-type cells, indicating that the two IFN systems are completely redundant in epithelia. Thus, influenza infection of airway epithelia induces, via a RIG-I/MAVS/IRF7 dependent pathway, both type I and III IFNs which drive two overlapping and redundant amplification loops to upregulate antiviral genes.
Published: 2013

34. The impact of macroautophagy on CD8 + T-cell-mediated antiviral immunity

Author: Matthew L. Albert, Brieuc Perot, Molly A. Ingersoll, Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), B. P. P. has received funding from Allocation doctorales Canceropole Ile-de-France. M. A. I. has received funding from the European Union Seventh Framework Programme Marie Curie Action under grant agreement no. [PCIG11-GA-2012-322117] and the Immuno-Oncology Labex. M. L. A. has received support from the European Research Council (ERC), the French National Cancer Institute (INCa) and La Ligue contre le cancer., The authors thank Monique Gannage and Pierre-Emmanuel Joubert for critical reading of the manuscript, European Project: 322117,EC:FP7:PEOPLE,FP7-PEOPLE-2012-CIG,UPECBCG(2013), and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Epitopes, T-Lymphocyte, MESH: Virus Diseases/immunology, CD8-Positive T-Lymphocytes, Lymphocyte Activation, MESH: CD8-Positive T-Lymphocytes/immunology, 0302 clinical medicine, T-Lymphocyte Subsets, Immunology and Allergy, MESH: Animals, MESH: Viruses/immunology, Antigens, Viral, MESH: CD8-Positive T-Lymphocytes/metabolism, MESH: Cross-Priming/immunology, 0303 health sciences, MESH: Epitopes, T-Lymphocyte/immunology, MESH: Autophagy/immunology, Acquired immune system, 3. Good health, Cell biology, Virus Diseases, Viruses, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Immunity, Innate, MESH: Virus Diseases/metabolism, MESH: Antigen Presentation/immunology, Immunology, Antigen presentation, virus, Biology, Major histocompatibility complex, 03 medical and health sciences, Immune system, Cross-Priming, Antigen, MESH: T-Lymphocyte Subsets/immunology, MHC class I, MESH: Antigens, Viral/immunology, Autophagy, Animals, Humans, 030304 developmental biology, Innate immune system, MESH: Humans, CD8+ T lymphocytes, Immunity, Innate, MESH: Lymphocyte Activation/immunology, macroautophagy, antigen presentation, biology.protein, 030215 immunology
Abstract: International audience; Macroautophagy is a catabolic recycling pathway, which can be induced by various stress stimuli. Viruses are able to manipulate autophagy in the cells that they infect. The impact of autophagy on the innate immune response to viruses and its stimulatory role in antigen presentation to CD4(+) T cells are well documented. Herein, we present the impact of autophagy on the activation of cytotoxic T lymphocyte (CTL)-mediated antiviral immune responses, which are required for the eradication or control of multiple viruses. We first discuss the general mechanisms by which viruses can either induce or block autophagy in cells. We then explore the cross-talk between autophagy and innate immune processes, which are both first line defenses against viruses; and constitute crucial steps for the initiation of potent adaptive immune responses. We describe the impact of autophagy on the presentation of viral peptide antigens on class I major histocompatibility complex (MHC I), a prerequisite for the priming of CTL responses. In sum, our review highlights the interplay between viruses and three integrated host response pathways - autophagy, innate and adaptive immunity - providing a framework for future mechanistic and pathogenesis-based research.
Published: 2013

35. Chikungunya Virus-associated Long-term Arthralgia: A 36-month Prospective Longitudinal Study

Author: Marc Lecuit, Florence Carpentier, Thérèse Couderc, Clémentine Schilte, Yoann Madec, Somar Kassab, Alain Michault, Matthew L. Albert, Frédérik Staikovsky, Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Emergency Department, Pôle des Spécialités de l'Urgence, Centre Hospitalier Régional de La Réunion (CHR Réunion), Biologie des Infections - Biology of Infection, Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), BIOlogie et GEstion des Risques en agriculture (BIOGER), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Microbiologie cellulaire et moléculaire et pathogénicité (MCMP), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Microorganismes et Barrières de l'Hôte (Equipe avenir), Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris]-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), This study was funded by the CRVOI (Centre de Recherche et de Veille sur les maladies émergentes dans l’Océan Indien), Institut Pasteur, Inserm (Institut National de la Santé et de la Recherche Médicale), Labex IBEID, Fondation pour la Recherche Médicale, BNP-Paribas Foundation and Mairie de Paris, ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ProdInra, Archive Ouverte, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Microbiologie Fondamentale et Pathogénicité (MFP), Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Epidémiologie des Maladies Emergentes, Pasteur-Cnam risques infectieux et émergents (PACRI), AgroParisTech-Institut National de la Recherche Agronomique (INRA), Equipe avenir Microorganismes et Barrières de l'Hôte, CHU Necker - Enfants Malades [AP-HP], ANR-10-LABX-62-IBEID,IBEID,Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases'(2010), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional de La Réunion ( CHR Réunion ), Biologie des Infections, Institut Pasteur [Paris]-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Institut Pasteur [Paris]-Pasteur-Cnam risques infectieux et émergents ( PACRI ), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] ( CNAM ), BIOlogie GEstion des Risques en agriculture - Champignons Pathogènes des Plantes ( BIOGER-CPP ), Institut National de la Recherche Agronomique ( INRA ) -AgroParisTech, CNRS-UMR 5234, Microbiologie fondamentale et Pathogénicité, University of Bordeaux 2, Bordeaux, France, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre Hospitalier Universitaire de La Réunion ( CHU La Réunion ), and ANR-10-LABX-62-IBEID,IBEID,Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases' ( 2010 )
Subjects: myalgia, Male, MESH: Alphavirus Infections/epidemiology, MESH : Aged, MESH : Prospective Studies, Disease, epidemic, Disease Outbreaks, La Réunion, 0302 clinical medicine, Chikungunya, Longitudinal Studies, Prospective Studies, skin and connective tissue diseases, MESH : Reunion/epidemiology, Aged, 80 and over, 0303 health sciences, MESH: Middle Aged, virus diseases, 3. Good health, [SDV] Life Sciences [q-bio], Cohort, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Medicine, musculoskeletal diseases, medicine.medical_specialty, MESH : Chikungunya Fever, lcsh:RC955-962, MESH : Cohort Studies, reunion Island, [ SDV.MP.VIR ] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Microbiology, 03 medical and health sciences, Rheumatology, Humans, MESH : Disease Outbreaks, MESH : Middle Aged, MESH : Aged, 80 and over, Biology, Aged, MESH: Humans, [ SDV ] Life Sciences [q-bio], Alphavirus Infections, MESH: Arthralgia/pathology, MESH : Humans, Public Health, Environmental and Occupational Health, lcsh:RA1-1270, MESH: Adult, infection, body regions, quality-of-life, Immunology, Complication, MESH: Female, MESH: Arthralgia/epidemiology, [SDV]Life Sciences [q-bio], MESH: Chikungunya Fever, MESH : Alphavirus Infections/epidemiology, medicine.disease_cause, Cohort Studies, MESH: Aged, 80 and over, MESH: Alphavirus Infections/complications, Risk Factors, MESH: Risk Factors, MESH : Female, MESH: Disease Outbreaks, MESH : Arthralgia/epidemiology, Prospective cohort study, risk-factors, MESH: Longitudinal Studies, musculoskeletal pain, MESH: Cohort Studies, Depression (differential diagnoses), MESH : Longitudinal Studies, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Aged, severe disease, lcsh:Public aspects of medicine, MESH : Adult, Middle Aged, MESH : Risk Factors, Arthralgia, Infectious Diseases, Female, medicine.symptom, Research Article, Neglected Tropical Diseases, Adult, lcsh:Arctic medicine. Tropical medicine, MESH : Male, 030231 tropical medicine, clinical-manifestations, MESH : Arthralgia/pathology, MESH : Alphavirus Infections/complications, MESH: Reunion/epidemiology, Internal medicine, medicine, 2005-2006 outbreak, 030304 developmental biology, business.industry, MESH: Male, MESH: Prospective Studies, Emerging Infectious Diseases, Chikungunya Fever, business, Reunion, Blood sampling
Abstract: Background Arthritogenic alphaviruses, including Chikungunya virus (CHIKV), are responsible for acute fever and arthralgia, but can also lead to chronic symptoms. In 2006, a Chikungunya outbreak occurred in La Réunion Island, during which we constituted a prospective cohort of viremic patients (n = 180) and defined the clinical and biological features of acute infection. Individuals were followed as part of a longitudinal study to investigate in details the long-term outcome of Chikungunya. Methodology/Principal Findings Patients were submitted to clinical investigations 4, 6, 14 and 36 months after presentation with acute CHIKV infection. At 36 months, 22 patients with arthralgia and 20 patients without arthralgia were randomly selected from the cohort and consented for blood sampling. During the 3 years following acute infection, 60% of patients had experienced symptoms of arthralgia, with most reporting episodic relapse and recovery periods. Long-term arthralgias were typically polyarthralgia (70%), that were usually symmetrical (90%) and highly incapacitating (77%). They were often associated with local swelling (63%), asthenia (77%) or depression (56%). The age over 35 years and the presence of arthralgia 4 months after the disease onset are risk factors of long-term arthralgia. Patients with long-term arthralgia did not display biological markers typically found in autoimmune or rheumatoid diseases. These data helped define the features of CHIKV-associated chronic arthralgia and permitted an estimation of the economic burden associated with arthralgia. Conclusions/Significance This study demonstrates that chronic arthralgia is a frequent complication of acute Chikungunya disease and suggests that it results from a local rather than systemic inflammation., Author Summary Chikungunya virus (CHIKV) is transmitted to human by mosquitoes. It is a re-emerging virus that has a risk to spread globally, given the expanding dissemination of its mosquito vectors. Chikungunya disease is characterized by acute transient febrile arthralgic illness, but can also lead to chronic incapacitating arthralgia. We have conducted a prospective longitudinal study to investigate in details long-term outcome of CHIKV infection. We found that 60% of patients experienced arthralgia 36 months after the onset of acute disease. Arthralgia affected most often multiple sites and were usually incapacitating. In addition to arthralgia, many patients suffered from myalgia and cutaneous lesions and several cognitive dysfunctions. We also showed that age over 35 years and the presence of arthralgia 4 months after the onset of disease are risk factors for long-term arthralgia. Patients with long-term arthralgia did not display biological markers typically found in autoimmune or rheumatoid diseases. This study demonstrates that chronic arthralgia is a frequent complication of acute Chikungunya disease and suggests that it results from a local rather than systemic inflammation.
Published: 2013

36. BCG-Mediated Bladder Cancer Immunotherapy: Identifying Determinants of Treatment Response Using a Calibrated Mathematical Model

Author: Matthew L. Albert, Alexander Bachmann, Claire Biot, Romulus Breban, Joel R. Gsponer, Cyrill A. Rentsch, University of Basel (Unibas), Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL), Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), This work was supported by La Ligue Contre le Cancer and Association pour la Recherche sur le Cancer. CAR acknowledges support from the Swiss National Foundation., Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Mines Paris - PSL (École nationale supérieure des mines de Paris), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), and Vougny, Marie-Christine
Subjects: Oncology, medicine.medical_treatment, 030232 urology & nephrology, lcsh:Medicine, Cancer immunotherapy, 0302 clinical medicine, MESH: Urinary Bladder Neoplasms/immunology, MESH: Models, Theoretical, Clinical endpoint, Medicine, lcsh:Science, Mathematical models, Bladder Cancer and Urothelial Neoplasias of the Urinary Tract, Multidisciplinary, MESH: BCG Vaccine/therapeutic use, MESH: Urinary Bladder Neoplasms/therapy, 3. Good health, Infectious Diseases, 030220 oncology & carcinogenesis, Cancer treatment, BCG Vaccine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunotherapy, Research Article, Tumor Immunology, medicine.medical_specialty, Treatment response, [SDV.IMM] Life Sciences [q-bio]/Immunology, Urology, Bladder, Immunology, MESH: Immunotherapy/methods, 03 medical and health sciences, Immune system, Internal medicine, Humans, Immune response, Biology, Bladder cancer, MESH: Humans, business.industry, lcsh:R, Immunity, Immunologic Subspecialties, Models, Theoretical, medicine.disease, Dwell time, Surgery, Regimen, Urinary Bladder Neoplasms, Clinical Immunology, lcsh:Q, Tumor resection, Infectious Disease Modeling, business, BCG vaccine
Abstract: International audience; Intravesical Bacillus Calmette Guérin (BCG) immunotherapy is considered the standard of care for treatment of non-muscle invasive bladder cancer; however the treatment parameters were established empirically. In order to evaluate potential optimization of clinical parameters of BCG induction therapy, we constructed and queried a new mathematical model. Specifically, we assessed the impact of (1) duration between resection and the first instillation; (2) BCG dose; (3) indwelling time; and (4) treatment interval of induction therapy – using cure rate as the primary endpoint. Based on available clinical and in vitro experimental data, we constructed and parameterized a stochastic mathematical model describing the interactions between BCG, the immune system, the bladder mucosa and tumor cells. The primary endpoint of the model was the probability of tumor extinction following BCG induction therapy in patients with high risk for tumor recurrence. We theoretically demonstrate that extending the duration between the resection and the first BCG instillation negatively influences treatment outcome. Simulations of higher BCG doses and longer indwelling times both improved the probability of tumor extinction. A remarkable finding was that an inter-instillation interval two times longer than the seven-day interval used in the current standard of care would substantially improve treatment outcome. We provide insight into relevant clinical questions using a novel mathematical model of BCG immunotherapy. Our model predicts an altered regimen that may decrease side effects of treatment while improving response to therapy.
Published: 2013

37. Chikungunya-induced cell death is limited by ER and oxidative stress-induced autophagy

Author: Lucie Peduto, Claire De La Calle, Florence Guivel-Benhassine, Scott W. Werneke, Beth Levine, Olivier Schwartz, Pierre Emmanuel Joubert, Matthew L. Albert, Deborah J. Lenschow, Alessandra Giodini, Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Washington University School of Medicine, University of Washington [Seattle], Centre d'immunologie humaine (CIH), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Développement des Tissus Lymphoïdes, Howard Hughes Medical Institute (HHMI), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité - Virus and immunity, and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: Programmed cell death, autophagy, chikungunya, [SDV]Life Sciences [q-bio], Cellular homeostasis, endoplasmic reticulum stress and oxidative stress, Biology, medicine.disease_cause, Models, Biological, Virus, Mice, 03 medical and health sciences, medicine, Animals, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Chikungunya, Molecular Biology, 030304 developmental biology, 0303 health sciences, Alphavirus Infections, Mechanism (biology), 030302 biochemistry & molecular biology, Autophagy, apoptosis, virus diseases, Cell Biology, Endoplasmic Reticulum Stress, 3. Good health, Cell biology, Oxidative Stress, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Apoptosis, Chikungunya Fever, Chikungunya virus, Oxidative stress
Abstract: International audience; It has been recognized that macroautophagy constitutes an important survival mechanism that allows both the maintenance of cellular homeostasis and the regulation of programmed cell death pathways (e.g., apoptosis). Although several pathogens have been described to induce autophagy, the prosurvival function of this process in infectious models remains poorly characterized. Our recent studies on chikungunya virus (CHIKV), the causative agent of major epidemics in India, Southeast Asia and southern Europe, reveal a novel mechanism by which autophagy limits the cytopathic effects of CHIKV by impinging upon virus-induced cell death pathways.
Published: 2012

38. A human coronavirus responsible for the common cold massively kills dendritic cells but not monocytes

Author: Matthew L. Albert, Frédéric Tangy, Astrid Vabret, Jean K. Millet, Valérie Lorin, Béatrice Nal, Pierre-Olivier Vidalain, Helen K. W. Law, Nicolas Escriou, Mariana Mesel-Lemoine, Génomique Virale et Vaccination, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre de recherche Université de Hong-Kong-Pasteur, Réseau International des Instituts Pasteur (RIIP), Department of Anatomy [HKU], The University of Hong Kong (HKU), Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche Risques Microbiens (U2RM), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Réseau International des Instituts Pasteur ( RIIP ) -Centre de Recherche Université de Hong-Kong-Pasteur, The University of Hong Kong ( HKU ), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Unité de Recherche Risques Microbiens ( U2RM ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ), RAFFINAGE (RAFFINAGE), Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Département de pharmacochimie moléculaire [1999-2015] (DPM [1999-2015]), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Service de Virologie [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Génétique Moléculaire des Virus Respiratoires, and Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Programmed cell death, Human coronavirus 229E, Fas Ligand Protein, Immunology, Common Cold, Antigens, CD34, Respiratory Mucosa, Biology, CD13 Antigens, Virus Replication, Dendritic cells, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Microbiology, [ SDV.MP.VIR ] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Giant Cells, Monocytes, TNF-Related Apoptosis-Inducing Ligand, 03 medical and health sciences, 0302 clinical medicine, Immune system, Antigen, Cytopathogenic Effect, Viral, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Coronavirus 229E, Human, Virology, Humans, 030304 developmental biology, 0303 health sciences, Syncytium, Cell Death, Tumor Necrosis Factor-alpha, virus diseases, Dendritic Cells, biology.organism_classification, 3. Good health, Virus-Cell Interactions, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Viral replication, Insect Science, Caspases, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Respiratory epithelium, Tumor necrosis factor alpha, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology
Abstract: Human coronaviruses are associated with upper respiratory tract infections that occasionally spread to the lungs and other organs. Although airway epithelial cells represent an important target for infection, the respiratory epithelium is also composed of an elaborate network of dendritic cells (DCs) that are essential sentinels of the immune system, sensing pathogens and presenting foreign antigens to T lymphocytes. In this report, we show that in vitro infection by human coronavirus 229E (HCoV-229E) induces massive cytopathic effects in DCs, including the formation of large syncytia and cell death within only few hours. In contrast, monocytes are much more resistant to infection and cytopathic effects despite similar expression levels of CD13, the membrane receptor for HCoV-229E. While the differentiation of monocytes into DCs in the presence of granulocyte-macrophage colony-stimulating factor and interleukin-4 requires 5 days, only 24 h are sufficient for these cytokines to sensitize monocytes to cell death and cytopathic effects when infected by HCoV-229E. Cell death induced by HCoV-229E is independent of TRAIL, FasL, tumor necrosis factor alpha, and caspase activity, indicating that viral replication is directly responsible for the observed cytopathic effects. The consequence of DC death at the early stage of HCoV-229E infection may have an impact on the early control of viral dissemination and on the establishment of long-lasting immune memory, since people can be reinfected multiple times by HCoV-229E.
Published: 2012

39. Preexisting BCG-Specific T Cells Improve Intravesical Immunotherapy for Bladder Cancer

Author: Cyrill A. Rentsch, George N. Thalmann, Lucie Peduto, Matthew L. Albert, Caroline Demangel, Hélène Jusforgues-Saklani, Charlotte Auriau, Alexander Bachmann, Joel R. Gsponer, Fabrice Lemaître, Frédéric D. Birkhäuser, Claire Biot, Philippe Bousso, MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL), Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Basel (Unibas), Department of urology, University of Bern, Dynamiques des Réponses Immunes, Immunobiologie de l'Infection, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Développement des Tissus Lymphoïdes, Université Paris Descartes - Paris 5 (UPD5), Work was funded by La Ligue Contre le Cancer and L’Institut National du Cancer and through the generosity of the Caisse de Retraite et de Prévoyance des Clercs et Employés de Notaires (M.L.A.) and the Swiss National Foundation (C.A.R.)., We thank all members of the Albert Laboratory, G. Milon, L. Majlessi, R. Simeone, R. Brosch, R. Breban, and H. Law for their support and advice. We also thank S. Leroy and A. Fontanet for assistance with statistical analyses. The Center for Human Immunology and the Animal Facilty at Institut Pasteur were instrumental for the studies. We thank C. Leclerc for providing the ascitic fluid clones GK1.5 and H35.17.2., Institut Pasteur [Paris] - Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] - Centre National de la Recherche Scientifique (CNRS), Mines Paris - PSL (École nationale supérieure des mines de Paris), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: T-Lymphocytes, 030232 urology & nephrology, Fluorescent Antibody Technique, MESH: Flow Cytometry, Mice, 0302 clinical medicine, MESH: Immunity, Innate/immunology, Medicine, MESH : Female, MESH: Animals, MESH: Fluorescent Antibody Technique, MESH: BCG Vaccine/therapeutic use, MESH : Immunity, Innate/immunology, MESH : Immunotherapy/methods, General Medicine, MESH: T-Lymphocytes/immunology, Flow Cytometry, MESH: Urinary Bladder Neoplasms/therapy, 3. Good health, Administration, Intravesical, medicine.anatomical_structure, MESH : Administration, Intravesical, 030220 oncology & carcinogenesis, MESH : T-Lymphocytes/immunology, BCG Vaccine, MESH : Urinary Bladder Neoplasms/therapy, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Immunotherapy, Lymph, medicine.symptom, Intravesical chemotherapy, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH : Flow Cytometry, T cell, Tumor resection, Urology, MESH: Immunotherapy/methods, Inflammation, MESH : Mice, Inbred C57BL, complex mixtures, 03 medical and health sciences, MESH: Mice, Inbred C57BL, MESH : Mice, Adjuvant therapy, Animals, Humans, In patient, MESH: Mice, MESH: Administration, Intravesical, Bladder cancer, MESH: Humans, business.industry, MESH : Humans, medicine.disease, MESH : BCG Vaccine/therapeutic use, Immunity, Innate, Mice, Inbred C57BL, MESH : Fluorescent Antibody Technique, Urinary Bladder Neoplasms, Immunology, MESH : Animals, business, MESH: Female
Abstract: Comment in Words of wisdom. Re: Preexisting BCG-specific T cells improve intravesical immunotherapy for bladder cancer. [Eur Urol. 2012] Bladder cancer: Pre-existing immunity to BCG can boost clinical response to intravesical therapy. [Nat Rev Urol. 2012]; International audience; Therapeutic intravesical instillation of bacillus Calmette-Guérin (BCG) is effective at triggering inflammation and eliciting successful tumor immunity in patients with non-muscle invasive bladder cancer, with 50 to 70% clinical response. Therapeutic success relies on repeated instillations of live BCG administered as adjuvant therapy shortly after tumor resection; however, the precise mechanisms remain unclear. Using an experimental model, we demonstrate that after a single instillation, BCG could disseminate to bladder draining lymph nodes and prime interferon-γ-producing T cells. Nonetheless, repeated instillations with live BCG were necessary for a robust T cell infiltration into the bladder. Parenteral exposure to BCG before instillation overcame this requirement; after the first intravesical instillation, BCG triggered a more robust acute inflammatory process and accelerated T cell entry into the bladder, as compared to the standard protocol. Moreover, parenteral exposure to BCG before intravesical treatment of an orthotopic tumor markedly improved response to therapy. Indeed, patients with sustained preexisting immunity to BCG showed a significant improvement in recurrence-free survival. Together, these data suggest that monitoring patients' response to purified protein derivative, and, in their absence, boosting BCG responses by parenteral exposure before intravesical treatment initiation, may be a safe and effective means of improving intravesical BCG-induced clinical responses
Published: 2012

40. Cutting Edge: Independent Roles for IRF-3 and IRF-7 in Hematopoietic and Nonhematopoietic Cells during Host Response to Chikungunya Infection

Author: Matthew L. Albert, Matthew R. Buckwalter, Michael S. Diamond, Olivier Schwartz, Melissa E. Laird, Clémentine Schilte, Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Washington University School of Medicine (WUSM), University of Washington [Seattle], Virus et Immunité, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], This work was supported by the Institut Pasteur, INSERM, the European Research Council, and the French National Research Agency., Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Interferon Regulatory Factor-7, [SDV]Life Sciences [q-bio], Cell, MESH: Fibroblasts/metabolism, MESH: Chikungunya Fever, MESH: Membrane Glycoproteins/genetics, medicine.disease_cause, MESH: Mice, Knockout, MESH: Animals, Newborn, Mice, 0302 clinical medicine, Immunology and Allergy, MESH: Hematopoietic Stem Cells/metabolism, Chikungunya, MESH: Bone Marrow Transplantation, Cells, Cultured, Bone Marrow Transplantation, Mice, Knockout, 0303 health sciences, Membrane Glycoproteins, Age Factors, Signal transducing adaptor protein, MESH: Membrane Glycoproteins/deficiency, MESH: Adaptor Proteins, Signal Transducing/physiology, MESH: Toll-Like Receptor 7/genetics, MESH: Alphavirus Infections/immunology, 3. Good health, Haematopoiesis, MESH: Myeloid Differentiation Factor 88/deficiency, MESH: Toll-Like Receptor 7/deficiency, medicine.anatomical_structure, Radiation Chimera, Host-Pathogen Interactions, MESH: Interferon Regulatory Factor-7/deficiency, [SDV.IMM]Life Sciences [q-bio]/Immunology, Signal transduction, Chikungunya virus, MESH: Cells, Cultured, MESH: Radiation Chimera, Immunology, MESH: Interferon Regulatory Factor-3/physiology, Biology, Virus, MESH: Chikungunya virus/growth & development, 03 medical and health sciences, Immune system, MESH: Interferon Regulatory Factor-3/genetics, MESH: Myeloid Differentiation Factor 88/genetics, MESH: Mice, Inbred C57BL, medicine, Animals, MESH: Chikungunya virus/immunology, Adaptor Proteins, Signal Transducing, 030304 developmental biology, MESH: Age Factors, MESH: Hematopoietic Stem Cells/virology, Alphavirus Infections, MESH: Host-Pathogen Interactions, Interferon-alpha, Fibroblasts, Hematopoietic Stem Cells, Mice, Inbred C57BL, MESH: Interferon-alpha/biosynthesis, Animals, Newborn, Toll-Like Receptor 7, Myeloid Differentiation Factor 88, Chikungunya Fever, Interferon Regulatory Factor-3, 030215 immunology, MESH: Interferon Regulatory Factor-3/deficiency
Abstract: The host response to Chikungunya virus is dependent on the direct action of type I IFN on infected nonhematopoietic cells. Prior studies have demonstrated that multiple host sensors coordinate an antiviral response; however, the tissue source(s) and signaling pathways for IFN production remain unknown. In this study, we demonstrate that IRF-3 and IRF-7 are functionally redundant, but lack of both factors results in lethal infection in adult mice. Reciprocal bone marrow chimeras indicated that IRF-3 or IRF-7 expression in either hematopoietic or nonhemotopoietic cell compartments was capable of inducing an antiviral response. Interestingly, redundancy of IRF-3 and IRF-7 was age dependent, as neonatal animals lacking either factor succumbed to infection. We further demonstrate that IPS-1 is essential in nonhematopoietic cells and preferentially required during early life. These results highlight the interplay between nonimmune and immune cells during Chikungunya virus infection and suggest an important role for nonhematopoietic cells as a critical source of IFN-α/β.
Published: 2012

41. Discrimination of agonist and antagonist forms of CXCL10 in biological samples

Author: M. Schmolz, Stanislas Pol, L. Stephen, Matthew L. Albert, James Mapes, Armanda Casrouge, Vincent Mallet, C. Pfister, A. Bisiaux, Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Myriad rules based medicine, CHU Rouen, Normandie Université (NU), Service d'hépatologie médicale [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Immunologie Humaine (CIH), The work was funded by grants obtained from L'Institut National du Cancer (INCA), the European Research Council (ERC) and a private donation from Caisse de Retraite et de Prévoyance des Clercs et Employés de Notaires (CRPCEN)., The authors would like to thank members of the Centre d'Immunology Humaine (CIH) and the Pôle Integré de Recherche Clinique (PIRC) Institut Pasteur, and the members of the Liver Unit, Hopital Cochin for support of this work., Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], and Centre d'Immunologie Humaine ( CIH )
Subjects: Male, MESH: Inflammation, MESH: Carcinoma, Transitional Cell/urine, MESH : Aged, MESH : Hepatitis C, Chronic/blood, Immunoenzyme Techniques, MESH: Protein Structure, Tertiary, 0302 clinical medicine, MESH : Culture Media, Conditioned/chemistry, MESH: Chemokine CXCL10/analysis, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Protein Isoforms, Multiplex, MESH: Protein Isoforms/immunology, MESH: Culture Media, Conditioned/chemistry, Aged, 80 and over, MESH: Recombinant Fusion Proteins/analysis, 0303 health sciences, MESH: Middle Aged, Antibodies, Monoclonal, Atopic dermatitis, MESH: Enzyme-Linked Immunosorbent Assay/methods, MESH : Protein Isoforms/immunology, Neoplasm Proteins, 3. Good health, MESH : Peptide Fragments/immunology, MESH: Urinary Bladder Neoplasms/urine, MESH : Antibodies, Monoclonal/immunology, bladder cancer, MESH : Protein Structure, Tertiary, Agonist, MESH: Chemokine CXCL10/immunology, MESH: Protein Isoforms/analysis, MESH: Hepatitis C, Chronic/blood, Recombinant Fusion Proteins, Immunology, MESH : Body Fluids/chemistry, 03 medical and health sciences, MESH: Peptide Fragments/immunology, MESH : Immunoenzyme Techniques/methods, MESH: Antibodies, Monoclonal/immunology, Humans, MESH : Middle Aged, MESH : Aged, 80 and over, MESH : Protein Processing, Post-Translational, Aged, MESH : Inflammation, MESH: Humans, MESH : Humans, MESH: Adult, MESH: Peptide Fragments/analysis, medicine.disease, Peptide Fragments, Protein Structure, Tertiary, Chemokine CXCL10, Urinary Bladder Neoplasms, chemokines/monokines, Culture Media, Conditioned, MESH: Dipeptidyl Peptidase 4/metabolism, MESH : Recombinant Fusion Proteins/analysis, MESH: Female, Biomarkers, MESH : Protein Isoforms/analysis, hepatitis C virus, MESH : Carcinoma, Transitional Cell/urine, Translational Studies, MESH: Body Fluids/chemistry, medicine.disease_cause, MESH: Neoplasm Proteins/urine, MESH: Aged, 80 and over, Immunology and Allergy, MESH : Female, BCG, MESH : Biomarkers, MESH: Aged, Predictive marker, MESH : Adult, Middle Aged, Body Fluids, MESH : Neoplasm Proteins/urine, MESH : Enzyme-Linked Immunosorbent Assay/methods, MESH : Chemokine CXCL10/immunology, Biomarker (medicine), [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Adult, medicine.drug_class, MESH : Male, Dipeptidyl Peptidase 4, Hepatitis C virus, Enzyme-Linked Immunosorbent Assay, MESH : Chemokine CXCL10/analysis, MESH : Dipeptidyl Peptidase 4/metabolism, medicine, MESH : Urinary Bladder Neoplasms/urine, MESH : Peptide Fragments/analysis, 030304 developmental biology, Inflammation, Carcinoma, Transitional Cell, business.industry, MESH: Immunoenzyme Techniques/methods, Cancer, Hepatitis C, Chronic, MESH: Male, Transplantation, MESH: Protein Processing, Post-Translational, MESH: Biomarkers, business, Protein Processing, Post-Translational, 030215 immunology
Abstract: Summary The ready access to commercially available multiplex assays and the importance of inflammation in disease pathogenesis has resulted in an abundance of studies aimed at identifying surrogate biomarkers for different clinically important questions. Establishing a link between a biomarker and disease pathogenesis, however, is quite complex, and in some instances this complexity is compounded by post-translational modifications and the use of immunoassays that do not always discriminate between the different forms of the same protein. Herein, we provide a detailed description of an assay system that has been established to discriminate the agonist form of CXCL10 from the NH2-terminal truncated form of the molecule generated by dipeptidylpeptidase IV (DPP4) cleavage. We demonstrate the utility of this assay system for monitoring agonist and antagonist forms of CXCL10 in culture supernatant, patient plasma and urine samples. Given the important role of CXCL10 in chronic inflammatory diseases and its suggested role as a predictive marker in managing patients with chronic hepatitis C, asthma, atopic dermatitis, transplantation, tuberculosis, kidney injury, cancer and other diseases, we believe that our method will be of general interest to the research and medical community.
Published: 2012

42. Mathematical model of tumor immunotherapy for bladder carcinoma identifies the limitations of the innate immune response

Author: Cyrill A. Rentsch, Matthew L. Albert, Romulus Breban, Claire Biot, Aurélie Bisiaux, Philippe Bousso, Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL), University of Basel (Unibas), Dynamiques des Réponses Immunes, This work was supported by La Ligue Contre le Cancer. CR acknowledges support from the Swiss National Foundation, Vougny, Marie-Christine, Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and MINES ParisTech - École nationale supérieure des mines de Paris
Subjects: bladder carcinoma, Innate immune system, [SDV.IMM] Life Sciences [q-bio]/Immunology, Effector, medicine.medical_treatment, Immunology, bystander death of tumor cell, CCL18, Degranulation, apoptosis, Immunotherapy, Biology, 3. Good health, Cytokine, Immune system, Oncology, Bystander effect, medicine, Immunology and Allergy, [SDV.IMM]Life Sciences [q-bio]/Immunology, innate immunity, mathematical model, Research Paper, BCG immunotherapy
Abstract: International audience; Treatment for non-muscle invasive carcinoma of the bladder represents one of the few examples of successful tumor immunity. Six weekly intravesical instillations of Bacillus Calmette-Guerin (BCG), often followed by maintenance schedule, result in up to 50-70% clinical response. Current models suggest that the mechanism of action involves the non-specific activation of innate effector cells, which may be capable of acting in the absence of an antigen-specific response. For example, recent evidence suggests that BCG-activated neutrophils possess anti-tumor potential. Moreover, weekly BCG treatment results in a prime-boost pattern with massive influx of innate immune cells (107-108 PMN/ml urine). Calibrating in vivo data, we estimate that the number of neutrophil degranulations per instillation is approximately 106-107, more than sufficient to potentially eliminate ~106 residual tumor cells. Furthermore, neutrophils, as well as other innate effector cells are not selective in their targeting-thus surrounding cells may be influenced by degranulation and / or cytokine production. To establish if these observed conditions could account for clinically effective tumor immunity, we built a mathematical model reflecting the early events and tissue conditioning in patients undergoing BCG therapy. The model incorporates key features of tumor growth, BCG instillations and the observed prime / boost pattern of the innate immune response. Model calibration established that each innate effector cell must kill 90-95 bystander cells for achieving the expected 50-70% clinical response. This prediction was evaluated both empirically and experimentally and found to vastly exceed the capacity of the innate immune system. We therefore conclude that the innate immune system alone is unable to eliminate the tumor cells. We infer that other aspects of the immune response (e.g., antigen-specific lymphocytes) decisively contribute to the success of BCG immunotherapy.
Published: 2012

43. Dying to Replicate: The Orchestration of the Viral Life Cycle, Cell Death Pathways, and Immunity

Author: Matthew L. Albert, Nader Yatim, Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Funding support is from the Agence National de Recherche (ANR) and the Immuno-Oncology LabEx Project, We would like to dedicate this review to the memory of R. Steinman, the consummate mentor and a leader in the field of dendritic cell biology and host response to infection. Far ahead of his time, he informed the dendritic cell community in 2000 that we must always consider the microbes agenda if we are going to understand how to vaccinate the host. His insights and support will be sorely missed. We would like to thank A. Oberst, O. Schwartz, and M. Laird for their careful read of the manuscript. We also acknowledge helpful discussions with L. Quintana-Murci, D. Green and members of his lab, and the Laboratory of Dendritic Cell Biology, ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: MESH: Cell Death, Programmed cell death, MESH: Virus Replication, Immunology, MESH: Biological Evolution, Biology, MESH: Immune System, Virus Replication, Virus, 03 medical and health sciences, 0302 clinical medicine, Immune system, Viral life cycle, Viral entry, Immunity, Autophagy, Immunology and Allergy, Animals, Humans, MESH: Autophagy, MESH: Animals, Permissive, 030304 developmental biology, 0303 health sciences, MESH: Humans, Cell Death, Virology, Biological Evolution, Chronic infection, MESH: Virus Physiological Phenomena, Infectious Diseases, 030220 oncology & carcinogenesis, Immune System, [SDV.IMM]Life Sciences [q-bio]/Immunology, Virus Physiological Phenomena
Abstract: International audience; Manipulation of cell death pathways has been identified as a common feature of host-microbe interactions. We examine two examples: influenza A as a representative acute infection and cytomegalovirus as an example of chronic infection. From the perspective of viral entry, replication, and transmission, we identify points of interconnection with the host response to infection, namely the induction of host cell death, inflammation, and immunity. Following from this analysis, we argue that the evolution and fine-tuned regulation of death-associated genes may result from constant microbial pressure--past and present--that helped to support and coordinate cell death programs within the host. Interestingly, the delay in host cell death allows time for the virus to replicate while perturbations in cell death allow the host cell to initiate an immune response. This may represent a genetically encoded trade-off ensuring survival of both host and virus, or it may be a part of the complex agenda of infectious microbes
Published: 2011

44. Innate sensing of HIV-infected cells

Author: Marion Sourisseau, Olivier Schwartz, Julien Pothlichet, Stephanie Louis, Mustapha Si-Tahar, Laurence Chaperot, Richard E. Randall, Helen K. W. Law, Alice Lepelley, Matthew L. Albert, Clémentine Schilte, Fabrizio Mammano, Joel Plumas, Virus et Immunité, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Centre d'immunologie humaine (CIH), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Défense innée et inflammation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Immunobiologie des Cellules Dendritiques, Université Joseph Fourier - Grenoble 1 (UJF), University of St Andrews [Scotland], University of St Andrews. School of Biology, University of St Andrews. Biomedical Sciences Research Complex, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Gau, Mireille
Subjects: HIV Infections, Virus Replication, RIG-I, 0302 clinical medicine, Interferon, HIV Seropositivity, Lymphocytes, lcsh:QH301-705.5, Cells, Cultured, 0303 health sciences, biology, Reverse Transcriptase Polymerase Chain Reaction, I interferon-production, Antiviral responses, virus diseases, 3. Good health, Integrase, Human-immunodeficiency-virus, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Plasmacytoid dendritic cells, Virology/Immunodeficiency Viruses, Viral-infection, QR355 Virology, medicine.drug, Research Article, lcsh:Immunologic diseases. Allergy, Immunology, Blotting, Western, Microbiology, Virus, 03 medical and health sciences, CD4(+) T-cells, SDG 3 - Good Health and Well-being, Virology, Genetics, medicine, Humans, RNA, Messenger, Adapter protein, Molecular Biology, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, 030304 developmental biology, Glycoproteins, QR355, Virion, HIV, Interferon-alpha, TLR7, Dendritic Cells, Hematopoietic Stem Cells, Reverse transcriptase, lcsh:Biology (General), Viral replication, Toll-Like Receptor 7, biology.protein, Parasitology, Interferon Regulatory Factor-3, Virology/Host Antiviral Responses, IFN-alpha, lcsh:RC581-607, IRF3, Alpha-interferon, 030215 immunology
Abstract: Cell-free HIV-1 virions are poor stimulators of type I interferon (IFN) production. We examined here how HIV-infected cells are recognized by plasmacytoid dendritic cells (pDCs) and by other cells. We show that infected lymphocytes are more potent inducers of IFN than virions. There are target cell-type differences in the recognition of infected lymphocytes. In primary pDCs and pDC-like cells, recognition occurs in large part through TLR7, as demonstrated by the use of inhibitors and by TLR7 silencing. Donor cells expressing replication-defective viruses, carrying mutated reverse transcriptase, integrase or nucleocapsid proteins induced IFN production by target cells as potently as wild-type virus. In contrast, Env-deleted or fusion defective HIV-1 mutants were less efficient, suggesting that in addition to TLR7, cytoplasmic cellular sensors may also mediate sensing of infected cells. Furthermore, in a model of TLR7-negative cells, we demonstrate that the IRF3 pathway, through a process requiring access of incoming viral material to the cytoplasm, allows sensing of HIV-infected lymphocytes. Therefore, detection of HIV-infected lymphocytes occurs through both endosomal and cytoplasmic pathways. Characterization of the mechanisms of innate recognition of HIV-infected cells allows a better understanding of the pathogenic and exacerbated immunologic events associated with HIV infection., Author Summary AIDS is characterized by a hyperactivation of the immune system. Innate and inflammatory responses, associated with an exacerbated production of cytokines like type I interferons (IFN) and of chemokines, deregulate the normal functioning of T lymphocytes and other cells. The events that trigger this inappropriate activation remain poorly understood. Plasmacytoid dendritic cells (pDCs) normally produce IFN when they encounter viruses. Here we examined how HIV-infected cells are recognized by pDCs, as well as by other immune and non-immune cells. We show that viruses transmitted via cell-to-cell contacts are more potent inducers of IFN than cell-free viral particles. In pDCs, recognition occurs in large part through TLR7, a cellular receptor detecting viral genetic materials after capture in intracellular vesicles. Donor cells expressing replication-defective viruses are also able to trigger IFN production by target cells. We further show that in TLR7-negative, non-hematopoietic cells an additional cytoplasmic pathway allows sensing of HIV-infected lymphocytes. Therefore, detection of HIV-infected lymphocytes occurs at different intracellular localizations, and does not require ongoing viral replication. Characterization of the mechanisms of innate HIV-1 recognition allows a better understanding of the pathology of HIV infection, and has consequences for the design of vaccine strategies.
Published: 2011

45. Harnessing Naturally Occurring Tumor Immunity: A Clinical Vaccine Trial in Prostate Cancer

Author: Julia Kaufman, Suyan Tian, Howard I. Scher, Mayu O. Frank, Salina Parveen, Susan F. Slovin, Michael J. Morris, Matthew L. Albert, Robert B. Darnell, Nathalie E. Blachère, Mayte Suárez-Fariñas, Laboratory of Molecular Neuro-oncology, Howard Hughes Medical Institute (HHMI)-Rockefeller University [New York], Rockefeller University [New York], Memorial Sloane Kettering Cancer Center [New York], and This work was supported by the Burroughs Wellcome Fund and Doris Duke Foundation (MLA), the National Institutes of Health (NIH) (R01 CA85784 to RBD), the Rockefeller University Hospital Clinical and Translational Science Awards (CTSA)(grant UL1 RR024143) from the National Center for Research Resources at the NIH, the Leslie Misrock Memorial Fund, and David H. Koch
Subjects: Non-Clinical Medicine/Research Methods, Male, MESH: Prostatic Neoplasms/drug therapy, Immunology/Immunomodulation, Cell- and Tissue-Based Therapy, MESH: Dendritic Cells/transplantation, lcsh:Medicine, Apoptosis, Prostate cancer, 0302 clinical medicine, MESH: Aged, 80 and over, MESH: Dendritic Cells/cytology, MESH: Cell- and Tissue-Based Therapy, lcsh:Science, Oncology/Prostate Cancer, Aged, 80 and over, MESH: Aged, 0303 health sciences, Multidisciplinary, MESH: Middle Aged, Immunogenicity, Vaccination, Cell Biology/Cellular Death and Stress Responses, Middle Aged, 3. Good health, Prostate-specific antigen, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Research Article, MESH: Cell Line, Tumor, Cancer Vaccines, 03 medical and health sciences, MESH: Prostatic Neoplasms/immunology, Immune system, Cell Line, Tumor, medicine, Humans, MESH: Cancer Vaccines/immunology, 030304 developmental biology, Aged, MESH: Humans, business.industry, MESH: Apoptosis, lcsh:R, Vaccine trial, MESH: Prostate-Specific Antigen/immunology, Prostatic Neoplasms, Dendritic cell, Dendritic Cells, MESH: Vaccination, Prostate-Specific Antigen, medicine.disease, MESH: Male, Immunology, MESH: Cancer Vaccines/therapeutic use, lcsh:Q, Mathematics/Statistics, business, MESH: Female, MESH: Dendritic Cells/immunology
Abstract: Background Studies of patients with paraneoplastic neurologic disorders (PND) have revealed that apoptotic tumor serves as a potential potent trigger for the initiation of naturally occurring tumor immunity. The purpose of this study was to assess the feasibility, safety, and immunogenicity of an apoptotic tumor-autologous dendritic cell (DC) vaccine. Methods and Findings We have modeled PND tumor immunity in a clinical trial in which apoptotic allogeneic prostate tumor cells were used to generate an apoptotic tumor-autologous dendritic cell vaccine. Twenty-four prostate cancer patients were immunized in a Phase I, randomized, single-blind, placebo-controlled study to assess the safety and immunogenicity of this vaccine. Vaccinations were safe and well tolerated. Importantly, we also found that the vaccine was immunogenic, inducing delayed type hypersensitivity (DTH) responses and CD4+ and CD8+ T cell proliferation, with no effect on FoxP3+ regulatory T cells. A statistically significant increase in T cell proliferation responses to prostate tumor cells in vitro (p = 0.002), decrease in prostate specific antigen (PSA) slope (p = 0.016), and a two-fold increase in PSA doubling time (p = 0.003) were identified when we compared data before and after vaccination. Conclusions An apoptotic cancer cell vaccine modeled on naturally occurring tumor immune responses in PND patients provides a safe and immunogenic tumor vaccine. (ClinicalTrials.gov number NCT00289341). Trial Registration ClinicalTrials.gov NCT00289341
Published: 2010

46. Signal 0 for guided priming of CTLs: NKT cells do it too

Author: Matthew L. Albert, Philippe Bousso, Dynamiques des Réponses Immunes, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunobiologie des Cellules Dendritiques, and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0303 health sciences, Antigen Presentation, Chemistry, Immunology, InformationSystems_INFORMATIONSTORAGEANDRETRIEVAL, Models, Immunological, Priming (immunology), Dendritic Cells, Natural killer T cell, Lymphocyte Activation, Cell biology, 03 medical and health sciences, 0302 clinical medicine, Cross-Priming, Immunology and Allergy, Animals, Humans, Natural Killer T-Cells, [SDV.IMM]Life Sciences [q-bio]/Immunology, InformationSystems_MISCELLANEOUS, CD8, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 030215 immunology, T-Lymphocytes, Cytotoxic
Abstract: The cross-priming of antigen-specific CD8+ T cells requires help. The mechanism by which natural killer T cells provide such help is now characterized.
Published: 2010

47. A whodunit: an appointment with death

Author: Alessandra Giodini, Matthew L. Albert, Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Cytotoxicity, Immunologic, 0303 health sciences, Psychoanalysis, Cell Death, genetic structures, business.industry, Immunology, Cellular pathways, education, Dendritic Cells, CD8-Positive T-Lymphocytes, 16. Peace & justice, 03 medical and health sciences, Cross-Priming, 0302 clinical medicine, Immunity, Animals, Humans, Immunology and Allergy, Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antigens, business, 030304 developmental biology, 030215 immunology
Abstract: International audience; This is the tale of murder, suicide, evolution, and resurrection, taking place in four parts, and all in the name of antigen cross-priming. We invite you to explore the dark mysteries lurking within each of us as you are guided through circuitous cellular pathways in a merciless fight for survival... with viral immunity being the grand finale?!
Published: 2010

48. Molecular Analyte Profiling of the Early Events and Tissue Conditioning Following Intravesical Bacillus Calmette-Guerin Therapy in Patients With Superficial Bladder Cancer

Author: Christine Sadorge, Aurélie Bisiaux, Stéphanie Thomas, Ahmed Eladaoui, Stéphane Béchet, Elaine B. Albert, Nicolas Thiounn, Huey-Hsuan Chang, Peter Albert, Marc-Olivier Timsit, Dominique Prié, Agnès Mogenet, James Mapes, Camille Baron, Jean-Louis Bresson, Matthew L. Albert, Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'urologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de recherche clinique / Centre d'investigation clinique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Rules Based Medicine, Inc., Centre de recherche Croissance et signalisation (UMR_S 845), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Vaccinale et Biomédicale (CRVBm), Institut Pasteur [Paris], Staten Island Urological, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Unité de reccherche clinique / Centre d'investigation clinique[CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre de recherche Croissance et signalisation ( UMR_S 845 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche Vaccinale et Biomédicale ( CRVBm ), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP]
Subjects: Male, Proteomics, Chemokine, Time Factors, Urology, Urinary system, medicine.medical_treatment, Inflammation, 03 medical and health sciences, 0302 clinical medicine, Adjuvants, Immunologic, medicine, Humans, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, 030304 developmental biology, Aged, 0303 health sciences, Toll-like receptor, Innate immune system, Urinary bladder, biology, business.industry, Immunotherapy, Middle Aged, Flow Cytometry, Blood proteins, 3. Good health, medicine.anatomical_structure, Administration, Intravesical, Urinary Bladder Neoplasms, 030220 oncology & carcinogenesis, Immunology, Cancer research, biology.protein, BCG Vaccine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, medicine.symptom, business
Abstract: International audience; PURPOSE:We characterized the innate immune response to intravesical bacillus Calmette-Guerin therapy using a systems approach based on proteomic and cytometric screens.MATERIALS AND METHODS:Blood and urine were collected from patients receiving intravesical bacillus Calmette-Guerin therapy before, and 2 and 4 hours after bacillus Calmette-Guerin treatment, at the first and third instillation. Proteomic and cytometry based screens were performed.RESULTS:Molecular analyte profiling revealed a prime/boost pattern to the innate response to intravesical bacillus Calmette-Guerin. We identified 36 statistically significant changes in the proteins induced during the third instillation compared to the initial treatment. These analytes were classified into 3 categories of 1) plasma proteins that leaked into the urine, 2) cytokines/chemokines produced locally during the first hours of inflammation and 3) other innate molecules that modulate the bladder microenvironment. To characterize the marked increase in the inflammatory response after multiple treatments we evaluated the cells present in the urine and again a prime/boost response was revealed. For the locally produced analytes it was possible to define the cell source(s) and, thus, provide a first generation map of what occurs during the initial phase of bacillus Calmette-Guerin therapy.CONCLUSIONS:This study provides in vivo information concerning the ability of bacillus Calmette-Guerin to sensitize the tissue microenvironment to enhance innate responses and establishes a framework for improving vaccination strategies while decreasing adverse events.
Published: 2009

49. Plasmacytoid dendritic cells move down on the list of suspects: In search of the immune pathogenesis of chronic hepatitis C

Author: Jérémie Decalf, Stanislas Pol, Matthew L. Albert, Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hépatologie médicale [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] - Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Cochin [AP-HP]
Subjects: [SDV.IMM] Life Sciences [q-bio]/Immunology, Disease, Virus, Pathogenesis, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Immune system, medicine, Humans, 030304 developmental biology, 0303 health sciences, Hepatology, business.industry, Ribavirin, Dendritic Cells, Hepatitis C, Dendritic cell, Hepatitis C, Chronic, medicine.disease, 3. Good health, chemistry, Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Viral disease, business, 030215 immunology
Abstract: International audience; Chronic hepatitis C is a major public health problem. Despite numerous clinical studies in humans and experimental observations made in chimpanzees, hepatitis C pathogenesis remains poorly understood. Here, we review the clinical features of acute and chronic disease, and discuss the role of the immune system in the pathogenesis of disease. Many are aware of the dual role of T cells: responsibility for clearance of the virus during acute phase; and liver injury during chronic phase. Nonetheless, there is an emerging belief that failure to prime HCV-specific T cells is responsible for the failure to spontaneously clear the virus, and possibly, for the lack of response to pegylated-IFNalpha(2a)/ribavirin therapy. We have focused on the latest suspects, plasmacytoid dendritic cells (pDCs), considered to be the professional type I IFNs producing cells. We review the somewhat contradictory data regarding the functional capacity of pDCs in chronic HCV patients and argue that, while lower in relative concentration as compared to healthy individuals, they are not defective in their ability to initiate an innate inflammatory response. Thus, instead of being the culprit, pDCs may in fact represent a novel therapeutic target in order to improve upon existing therapies for treating HCV patients.
Published: 2008

50. Selection of high-avidity CD8 T cells correlates with control of hepatitis C virus infection

Author: E. Debeaupuis, Michelle Gassin, Jérémie Decalf, Xavier Saulquin, Jérôme Gournay, Béatrice Le Moullac-Vaidye, Elisabeth Houssaint, Matthew L. Albert, Klara Echasserieau, Loïg Jegou, Nicolas Ferry, B. Neveu, Marc Bonneville, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de virologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hépato-gastro-entérologie, cancérologie digestive et assistance nutritionnelle [CHU de Nantes], Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN), Supported by Agence Nationale de la Recherche sur le SIDA, Agence Nationale de la Recherche, Ligue Départementale Contre le Cancer, Fondation pour la Recherche Médicale, grants from Institut National de la Santé et de la Recherche Médicale, and Université de Nantes., and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Genotype, T cell, Antibody Affinity, Receptors, Antigen, T-Cell, Epitopes, T-Lymphocyte, Hepacivirus, Biology, CD8-Positive T-Lymphocytes, Epitope, Cell Line, 03 medical and health sciences, Interleukin 21, Interferon-gamma, 0302 clinical medicine, Antigen, HLA-A2 Antigen, medicine, Cytotoxic T cell, Humans, Avidity, 030304 developmental biology, 0303 health sciences, Immunity, Cellular, Hepatology, HLA-A Antigens, Tumor Necrosis Factor-alpha, T-cell receptor, T lymphocyte, Virology, Hepatitis C, 3. Good health, medicine.anatomical_structure, Case-Control Studies, Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, 030215 immunology, T-Lymphocytes, Cytotoxic
Abstract: International audience; Both strong antigenic avidity and acquisition of proper effector functions contribute to the efficacy of antiviral T cell responses. To correlate these parameters with the outcome of hepatitis C virus (HCV) infection, we characterized HCV-specific CD8 T cell lines isolated after immunomagnetic sorting of peripheral blood mononuclear cells from human leukocyte antigen A*02 (HLA-A*02) individuals with various HCV serological statuses, using recombinant HLA-A*0201 multimers loaded with three immunodominant HCV genotype 1-derived epitopes. CD8 T cells specific for these three epitopes were derived from most HLA-A*0201 individuals, regardless of their HCV serology or clinical outcome. Donors recovered from genotype 1 HCV infection were enriched for high-avidity T cells with enhanced interferon gamma (IFN-gamma), tumor necrosis factor alpha, and cytotoxic T lymphocyte responses, when compared with seronegative donors and seropositive patients infected with irrelevant HCV genotypes. Patients chronically infected with genotype 1 strain yielded almost exclusively low-avidity T cells, whose hyporesponsiveness was primarily attributable to low T cell receptor (TCR) avidity rather than intrinsic functional defects.CONCLUSION:This study suggests that strong IFN-gamma responses associated with efficient viral clearance primarily result from Ag-driven selection/survival of HCV-specific T cells expressing high-avidity TCR. It also suggests a link between the quality of the initial HCV-specific T cell repertoire and susceptibility to chronic infection.
Published: 2008

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