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1. Defective activation and regulation of type I interferon immunity is associated with increasing COVID-19 severity

Author: Nikaïa Smith, Céline Possémé, Vincent Bondet, Jamie Sugrue, Liam Townsend, Bruno Charbit, Vincent Rouilly, Violaine Saint-André, Tom Dott, Andre Rodriguez Pozo, Nader Yatim, Olivier Schwartz, Minerva Cervantes-Gonzalez, Jade Ghosn, Paul Bastard, Jean Laurent Casanova, Tali-Anne Szwebel, Benjamin Terrier, Niall Conlon, Cliona O’Farrelly, Clíona Ní Cheallaigh, Nollaig M. Bourke, and Darragh Duffy
Subjects: Science
Abstract: The interferon response has been shown to be linked to severity of SARS-CoV-2 infection and is an essential component of the immune response to COVID-19. Here the authors stratify patients according to COVID-19 severity and asses the interferon response showing defective responses in severe infection and highlight the importance of assay variables and confounding factors that impact the detection of interferon.
Published: 2022
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2. Tuberculosis alters immune-metabolic pathways resulting in perturbed IL-1 responses

Author: Alba Llibre, Nikaïa Smith, Vincent Rouilly, Munyaradzi Musvosvi, Elisa Nemes, Céline Posseme, Simbarashe Mabwe, Bruno Charbit, Stanley Kimbung Mbandi, Elizabeth Filander, Hadn Africa, Violaine Saint-André, Vincent Bondet, Pierre Bost, Humphrey Mulenga, Nicole Bilek, Matthew L. Albert, Thomas J. Scriba, and Darragh Duffy
Subjects: tuberculosis, IL-1ra, IL-1, immunometabolism, systems immunology, Immunologic diseases. Allergy, RC581-607
Abstract: Tuberculosis (TB) remains a major public health problem and we lack a comprehensive understanding of how Mycobacterium tuberculosis (M. tb) infection impacts host immune responses. We compared the induced immune response to TB antigen, BCG and IL-1β stimulation between latently M. tb infected individuals (LTBI) and active TB patients. This revealed distinct responses between TB/LTBI at transcriptomic, proteomic and metabolomic levels. At baseline, we identified a novel immune-metabolic association between pregnane steroids, the PPARγ pathway and elevated plasma IL-1ra in TB. We observed dysregulated IL-1 responses after BCG stimulation in TB patients, with elevated IL-1ra responses being explained by upstream TNF differences. Additionally, distinct secretion of IL-1α/IL-1β in LTBI/TB after BCG stimulation was associated with downstream differences in granzyme mediated cleavage. Finally, IL-1β driven signalling was dramatically perturbed in TB disease but was completely restored after successful treatment. This study improves our knowledge of how immune responses are altered during TB disease, and may support the design of improved preventive and therapeutic tools, including host-directed strategies.
Published: 2022
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3. Standardized Whole-Blood Transcriptional Profiling Enables the Deconvolution of Complex Induced Immune Responses

Author: Alejandra Urrutia, Darragh Duffy, Vincent Rouilly, Céline Posseme, Raouf Djebali, Gabriel Illanes, Valentina Libri, Benoit Albaud, David Gentien, Barbara Piasecka, Milena Hasan, Magnus Fontes, Lluis Quintana-Murci, Matthew L. Albert, Laurent Abel, Andres Alcover, Kalla Astrom, Philippe Bousso, Pierre Bruhns, Ana Cumano, Caroline Demangel, Ludovic Deriano, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay, Antonio Freitas, Odile Gelpi, Ivo Gomperts-Boneca, Serge Hercberg, Olivier Lantz, Claude Leclerc, Hugo Mouquet, Sandra Pellegrini, Stanislas Pol, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Vassili Soumelis, Frédéric Tangy, Eric Tartour, Antoine Toubert, and Marie-Noëlle Ungeheuer
Subjects: Biology (General), QH301-705.5
Abstract: Systems approaches for the study of immune signaling pathways have been traditionally based on purified cells or cultured lines. However, in vivo responses involve the coordinated action of multiple cell types, which interact to establish an inflammatory microenvironment. We employed standardized whole-blood stimulation systems to test the hypothesis that responses to Toll-like receptor ligands or whole microbes can be defined by the transcriptional signatures of key cytokines. We found 44 genes, identified using Support Vector Machine learning, that captured the diversity of complex innate immune responses with improved segregation between distinct stimuli. Furthermore, we used donor variability to identify shared inter-cellular pathways and trace cytokine loops involved in gene expression. This provides strategies for dimension reduction of large datasets and deconvolution of innate immune responses applicable for characterizing immunomodulatory molecules. Moreover, we provide an interactive R-Shiny application with healthy donor reference values for induced inflammatory genes.
Published: 2016
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4. In situ tumour arrays reveal early environmental control of cancer immunity

Author: Guadalupe Ortiz-Muñoz, Markus Brown, Catherine B. Carbone, Ximo Pechuan-Jorge, Vincent Rouilly, Henrik Lindberg, Alex T. Ritter, Gautham Raghupathi, Qianbo Sun, Tess Nicotra, Shreya R. Mantri, Angela Yang, Jonas Doerr, Deepti Nagarkar, Spyros Darmanis, Benjamin Haley, Sanjeev Mariathasan, Yulei Wang, Carlos Gomez-Roca, Carlos Eduardo de Andrea, David Spigel, Thomas Wu, Lelia Delamarre, Johannes Schöneberg, Zora Modrusan, Richard Price, Shannon J. Turley, Ira Mellman, and Christine Moussion
Subjects: Multidisciplinary
Abstract: The immune phenotype of a tumour is a key predictor of its response to immunotherapy1–4. Patients who respond to checkpoint blockade generally present with immune-inflamed5–7 tumours that are highly infiltrated by T cells. However, not all inflamed tumours respond to therapy, and even lower response rates occur among tumours that lack T cells (immune desert) or that spatially exclude T cells to the periphery of the tumour lesion (immune excluded)8. Despite the importance of these tumour immune phenotypes in patients, little is known about their development, heterogeneity or dynamics owing to the technical difficulty of tracking these features in situ. Here we introduce skin tumour array by microporation (STAMP)—a preclinical approach that combines high-throughput time-lapse imaging with next-generation sequencing of tumour arrays. Using STAMP, we followed the development of thousands of arrayed tumours in vivo to show that tumour immune phenotypes and outcomes vary between adjacent tumours and are controlled by local factors within the tumour microenvironment. Particularly, the recruitment of T cells by fibroblasts and monocytes into the tumour core was supportive of T cell cytotoxic activity and tumour rejection. Tumour immune phenotypes were dynamic over time and an early conversion to an immune-inflamed phenotype was predictive of spontaneous or therapy-induced tumour rejection. Thus, STAMP captures the dynamic relationships of the spatial, cellular and molecular components of tumour rejection and has the potential to translate therapeutic concepts into successful clinical strategies.
Published: 2023

5. Tuberculosis alters immune-metabolic pathways resulting in perturbed IL-1 responses

Author: Nicole Bilek, Violaine Saint-André, Elisa Nemes, Stanley Kimbung Mbandi, Elizabeth Filander, Munyaradzi Musvosvi, Humphrey Mulenga, Matthew L. Albert, Alba Llibre, Vincent Rouilly, Hadn Africa, Céline Posseme, Simba Mabwe, Nikaïa Smith, Vincent Bondet, Thomas J. Scriba, Pierre Bost, Darragh Duffy, Bruno Charbit, Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP), Datactix, University of Cape Town, Ecole Doctorale Complexité du Vivant (ED515), Sorbonne Université (SU), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Département de Biologie Computationnelle - Department of Computational Biology, Insitro [San Francisco], This study was funded by the Bill and Melinda Gates Foundation (OPP1114368 and OPP1204624), with additional support from the French Government’s Investissement d’Avenir Program, Laboratoire d’Excellence 'Milieu Intérieur' Grant ANR-10-LABX-69-01. AL was supported by the Fondation Recherche Médicale (SPF20170938617) and the European Commision (H2020-MSCA-IF 2018, 841729). NS was supported by an Institut Pasteur Roux Cantarini fellowship., We thank the UTechS CB of the Center for Translational Research, Institut Pasteur for supporting Nanostring analysis. DD thanks Immunoqure for provision of the mAbs under an MTA for the Simoa IFN-α assay. We are grateful to the study participants and the SATVI clinical and laboratory teams., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Institut Pasteur [Paris], and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: Tuberculosis, Immunology, Disease, Mycobacterium tuberculosis, 03 medical and health sciences, 0302 clinical medicine, Immune system, Antigen, Interleukin 1 (IL-1), Medicine, Immunology and Allergy, Interleukin 1 Receptor antagonist (IL-1ra), 030304 developmental biology, Systems immunology, 0303 health sciences, Immunometabolism, biology, business.industry, biology.organism_classification, medicine.disease, 3. Good health, Granzyme, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, business, 030215 immunology
Abstract: SUMMARYTuberculosis (TB) remains a major public health problem with host-directed therapeutics offering potential as novel treatment strategies. However, their successful development still requires a comprehensive understanding of howMycobacterium tuberculosis(M.tb) infection impacts immune responses. To address this challenge, we applied standardised immunomonitoring tools to compare TB antigen, BCG and IL-1β induced immune responses between individuals with latentM.tbinfection (LTBI) and active TB disease, at diagnosis and after cure. This revealed distinct responses between TB and LTBI groups at transcriptomic, proteomic and metabolomic levels. At baseline, we identified pregnane steroids and the PPARγ pathway as new immune-metabolic drivers of elevated plasma IL-1ra in TB. We also observed dysregulated induced IL-1 responses after BCG stimulation in TB patients. Elevated IL-1 antagonist responses were explained by upstream differences in TNF responses, while for IL-1 agonists it was due to downstream differences in granzyme mediated cleavage. Finally, the immune response to IL-1β driven signalling was also dramatically perturbed in TB disease but was completely restored after successful antibiotic treatment. This systems immunology approach improves our knowledge of how immune responses are altered during TB disease, and may support design of improved diagnostic, prophylactic and therapeutic tools.
Published: 2022

6. iBRAIN2: Automated analysis and data handling for RNAi screens.

Author: Vincent Rouilly, Eva Pujadas, Béla Hullár, Csaba Balázs, Peter Z. Kunszt, and Michael Podvinec
Published: 2012
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7. Defective type I interferon immunity is associated with increasing COVID-19 severity

Author: Darragh Duffy, Nikaïa SMITH, Céline Possémé, Vincent Bondet, Jamie Sugrue, Liam Townsend, Bruno Charbit, Vincent Rouilly, Violaine Saint-André, Tom Dott, Andre Rodriguez Pozo, Nader Yatim, Olivier Schwartz, Minerva Cervantes-Gonzales, Jade Ghosn, Paul Bastard, Jean-Laurent Casanova, Tali-Anne Szwebel, Benjamin Terrier, Niall Conlon, Cliona O'Farrelly, Cliona Ni Cheallaigh, Nollaig Bourke, Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP), Trinity College Dublin, Datactix, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Cochin [AP-HP], St James' Hospital, This study was supported by the 'URGENCE COVID-19' fundraising campaign the Institut Pasteur (CoVarImm and Steroid Response), from the Agence Nationale de la Recherche (ANR-flash COVID-19), by the Laboratoire d’Excellence ‘Milieu Intérieur’ (grant no. ANR-10-LABX-69-01), the Fonds IMMUNOV for Innovation in Immunopathology, and Science Foundation Ireland. We thank the STTAR-Bioresource of TCD-SJH-TUH COVID-19 bioresource which supported collection of patient samples. NS is a recipient of the Pasteur-Roux-Cantarini Fellowship. COF, NC and CNC are part-funded by a Science Foundation Ireland (SFI) grant, Grant Code 20/SPP/3685. LT is supported by the Irish Clinical Academic Training (ICAT) Programme, supported by the Wellcome Trust and the Health Research Board (Grant Number 203930/B/16/Z), the Health Service Executive, National Doctors Training and Planning and the Health and Social Care, Research and Development Division, Northern Ireland. N.B. is funded under the Science Foundation Ireland Phase 2 COVID-19 Rapid Response Call (20/COV/8487) and the Health Research Board COVID-19 Rapid Response Call (COV19e2020e053). The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI088364 and R01AI163029), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1 TR001866), a Fast Grant from Emergent Ventures, Mercatus Center at George Mason University, the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the JPB Foundation, the French National Research Agency (ANR) under the 'Investments for the Future' program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003), ANR AABIFNCOV (ANR-20-CO11-0001) and ANR GenMISC (ANR-21-COVR-0039) projects, the European Union’s Horizon 2020 research and innovation programme under grant agreement No 824110 (EASI-genomics), the Square Foundation, Grandir - Fonds de solidarité pour l’enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, The French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), Institut National de la Santé et de la Recherche Médicale (INSERM), REACTing-INSERM and the University of Paris. PB was supported by the MD-PhD program of the Imagine Institute (with the support of the Fondation Bettencourt-Schueller)., We thank the UTechS CB of the Center for Translational Research, Institut Pasteur for supporting Luminex and Nanostring analysis. We acknowledge all health-care workers involved in the diagnosis and treatment of patients in Hopital Cochin, Hopital Bichat, and St James’s Hospital Dublin., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-20-CE93-0003,GENVIR,Analyse multi-omique de l'immunité anti-virale: de l'identification des circuits biologiques pertinents à la découverte de défauts monogéniques héréditaires de l'immunité chez les patients avec infections virales sévères(2020), ANR-20-CO11-0001,AABIFNCOV,Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19.(2020), ANR-21-COVR-0039,GenMIS-C,Recherche des Déficits immunitaires innées monogéniques prédisposant au syndrome inflammatoire multisystémique chez l'enfant.(2021), European Project: 824110,H2020-INFRAIA-2018-1,EASI-Genomics(2019), Institut Pasteur [Paris]-Université Paris Cité (UPC), Institut Pasteur [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC)
Subjects: [SDV]Life Sciences [q-bio]
Abstract: Host immunity to infection with SARS-CoV-2 is highly variable, dictating diverse clinical outcomes ranging from asymptomatic to severe disease and death. We previously reported that reduced blood type I interferon (IFN-I) in severe COVID-19 patients preceded clinical worsening. These results were supported by studies which identified genetic mutations in loci of the TLR3- or TLR7-dependent IFN-I pathways, or autoantibodies neutralizing IFNα or IFNω, as major risk factors for development of severe and critical COVID-19 pneumonia. Here, we analyzed a range of IFN-I associated responses in patient cohorts with different severities of COVID-19, showing that baseline plasma IFNα measures differed significantly according to the immunoassay used, as well as timing of sampling, the IFNα subtype measured, and the presence of autoantibodies. We then compared immune responses induced by ex vivo stimulation between non-hospitalized moderate cases (n=27) and hospitalized (n=17) adult patients that required oxygen supplementation. This showed a consistently reduced induction of IFN-I proteins in hospitalized COVID-19 patients upon stimulation, that was not associated with detectable neutralizing autoantibodies against IFNα or IFNω. We confirmed the poor induction of IFN-I in an independent patient cohort (n=33), and showed it was more pronounced with severe disease. Intracellular proteomic analysis showed that while monocyte numbers were increased in hospitalized COVID-19 patients, they did not secrete IFN-I in response to stimulation. This was further confirmed by ex vivo whole blood stimulation with IFN-I which induced a transcriptomic response associated with inflammation in hospitalized COVID-19 patients, that was not seen in controls or non-hospitalized moderate cases. These results may explain the dichotomy of the poor clinical response to IFN-I based treatments in late stage COVID-19, despite the critical importance of IFN-I in early acute infection. An improved understanding of such variable responses to treatment may help to identify potential alternative therapeutic strategies.
Published: 2022

8. Immune Profiling Enables Stratification of Patients With Active Tuberculosis Disease or Mycobacteriu m tuberculosis Infection

Author: Françoise Dromer, Antonio Rausell, Elizabeth Filander, Bruno Charbit, Odile Gelpi, Kalla Astrom, Stanislas Pol, Elisa Nemes, Vincent Rouilly, Mark Hatherill, Hadn Africa, Humphrey Mulenga, Ana Cumano, Hugo Mouquet, Etienne Patin, Lluis Quintana-Murci, Lungisa Jaxa, Laurent Abel, Milena Hasan, James P. Di Santo, Claude Leclerc, Spencer L. Shorte, Vassili Soumelis, Stéphanie Thomas, Caroline Demangel, Mathilde Touvier, Andrés Alcover, Thomas J. Scriba, Matthew L. Albert, Anavaj Sakuntabhai, Hugues Aschard, Nikaïa Smith, Serge Hercberg, Darragh Duffy, Jost Enninga, Olivier Schwartz, Ivo Gomperts-Boneca, Marie-Noëlle Ungeheuer, Simbarashe Mabwe, Ludovic Deriano, Frédéric Tangy, Gérard Eberl, Sandra Pellegrini, Antoine Toubert, Lars Rogge, Stephanus T. Malherbe, Gerhard Walzl, Michele Tameris, Munyaradzi Musvosvi, Alba Llibre, Benno Schwikowski, Olivier Lantz, Nicole Bilek, Philippe Bousso, Pierre Bruhns, Jacques Fellay, and Eric Tartour
Subjects: 0301 basic medicine, Microbiology (medical), Tuberculosis, Enzyme-Linked Immunosorbent Assay, Disease, Asymptomatic, QuantiFERON, Mycobacterium tuberculosis, Interferon-gamma, 03 medical and health sciences, 0302 clinical medicine, Antigen, Latent Tuberculosis, medicine, Humans, 030212 general & internal medicine, Online only Articles, Whole blood, biology, business.industry, immune profiling, biomarkers, patient stratification, bacterial infections and mycoses, medicine.disease, biology.organism_classification, cytokines, 3. Good health, AcademicSubjects/MED00290, 030104 developmental biology, Infectious Diseases, Cohort, Immunology, medicine.symptom, business, Interferon-gamma Release Tests
Abstract: Background Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) infection and is a major public health problem. Clinical challenges include the lack of a blood-based test for active disease. Current blood-based tests, such as QuantiFERON (QFT) do not distinguish active TB disease from asymptomatic Mtb infection. Methods We hypothesized that TruCulture, an immunomonitoring method for whole-blood stimulation, could discriminate active disease from latent Mtb infection (LTBI). We stimulated whole blood from patients with active TB and compared with LTBI donors. Mtb-specific antigens and live bacillus Calmette-Guérin (BCG) were used as stimuli, with direct comparison to QFT. Protein analyses were performed using conventional and digital enzyme-linked immunosorbent assay (ELISA), as well as Luminex. Results TruCulture showed discrimination of active TB cases from LTBI (P < .0001, AUC = .81) compared with QFT (P = .45, AUC = .56), based on an interferon γ (IFNγ) readout after Mtb antigen (Ag) stimulation. This result was replicated in an independent cohort (AUC = .89). In exploratory analyses, TB stratification could be further improved by the Mtb antigen to BCG IFNγ ratio (P < .0001, AUC = .91). Finally, the combination of digital ELISA and transcriptional analysis showed that LTBI donors with high IFNγ clustered with patients with TB, suggesting the possibility to identify subclinical disease. Conclusions TruCulture offers a next-generation solution for whole-blood stimulation and immunomonitoring with the possibility to discriminate active and latent infection., We tested TruCulture, an immunomonitoring tool, to identify active disease from latent Mtb infection. TruCulture showed improved discrimination of tuberculosis cases from LTBI as compared with QuantiFERON. Tuberculosis stratification could be further improved by the Mtb Ag:BCG IFNγ ratio.
Published: 2020

9. Polygenic risk for skin autoimmunity impacts immune checkpoint blockade in bladder cancer

Author: Magnus Fontes, Sergio Ley Acosta, Ellie Guardino, Sanjeev Mariathasan, Matthew L. Albert, Vincent Rouilly, Christian Hammer, G. Scott Chandler, Jonathan Rosenberg, J. D. Carroll, Ira Mellman, Antonia Kwan, Tushar Bhangale, Haiyin Chen-Harris, Julie Hunkapiller, Thomas Powles, Zia Khan, and F. Di Nucci
Subjects: Oncology, medicine.medical_specialty, Multidisciplinary, Bladder cancer, business.industry, Cancer, Atopic dermatitis, Vitiligo, medicine.disease, Immune checkpoint, Atezolizumab, Psoriasis, Internal medicine, Medicine, Adverse effect, business, Cancer immunology
Abstract: PD-1 and PD-L1 act to restrict T-cell responses in cancer and contribute to self-tolerance. Consistent with this role, PD-1 checkpoint inhibitors have been associated with immune-related adverse events (irAEs), immune toxicities thought to be autoimmune in origin. Analyses of dermatological irAEs have identified an association with improved overall survival (OS) following anti-PD-(L)1 therapy, but the factors that contribute to this relationship are poorly understood. We collected germline whole genome sequencing data from IMvigor211, a recent phase 3 randomized controlled trial comparing atezolizumab (anti-PD-L1) monotherapy to chemotherapy in bladder cancer. We found that high vitiligo, high psoriasis, and low atopic dermatitis polygenic risk scores (PRSs) were associated with longer OS under anti-PD-L1 monotherapy as compared to chemotherapy, reflecting the Th17 polarization of these diseases. PRSs were not correlated with tumor mutation burden, PD-L1 immunohistochemistry, nor T-effector gene signatures. Shared genetic factors impact risk for dermatological autoimmunity and anti-PD-L1 monotherapy in bladder cancer.
Published: 2020

10. SCHNAPPs - Single Cell sHiNy APPlication(s)

Author: Bernd, Jagla, Valentina, Libri, Claudia, Chica, Vincent, Rouilly, Sebastien, Mella, Michel, Puceat, Milena, Hasan, Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Datactix, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), We would like to thank the members of Single-cell working group Pasteur/Paris for helpful discussions: Anna Barcons, Eric Tartour, Antonin Saldmann, Mandar Patgaonkar, Lisa Chakrabarti, and James Di Santo for testing and working with scShinyHub and SCHNAPPs. Kenneth Smith and Christian Vosshenrich for careful reading of the manuscript. We thank the ICAReB platform of the Institut Pasteur for providing blood samples from healthy individuals., Institut Pasteur [Paris], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), and Chica, Claudia
Subjects: MESH: Humans, Sequence Analysis, RNA, CITE-Seq, Shiny application, MESH: Leukocytes, Mononuclear, MESH: Software, scRNA-seq, Leukocytes, Mononuclear, MESH: Sequence Analysis, RNA, Humans, Single-Cell Analysis, multi-omics data analysis, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Software, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Single-Cell Analysis
Abstract: International audience; Single-cell RNA-sequencing (scRNAseq) experiments are becoming a standard tool for bench-scientists to explore the cellular diversity present in all tissues. Data produced by scRNAseq is technically complex and requires analytical workflows that are an active field of bioinformatics research, whereas a wealth of biological background knowledge is needed to guide the investigation. Thus, there is an increasing need to develop applications geared towards bench-scientists to help them abstract the technical challenges of the analysis so that they can focus on the science at play. It is also expected that such applications should support closer collaboration between bioinformaticians and bench-scientists by providing reproducible science tools. We present SCHNAPPs, a Graphical User Interface (GUI), designed to enable bench-scientists to autonomously explore and interpret scRNAseq data and associated annotations. The R/Shiny-based application allows following different steps of scRNAseq analysis workflows from Seurat or Scran packages: performing quality control on cells and genes, normalizing the expression matrix, integrating different samples, dimension reduction, clustering, and differential gene expression analysis. Visualization tools for exploring each step of the process include violin plots, 2D projections, Box-plots, alluvial plots, and histograms. An R-markdown report can be generated that tracks modifications and selected visualizations. The modular design of the tool allows it to easily integrate new visualizations and analyses by bioinformaticians. We illustrate the main features of the tool by applying it to the characterization of T cells in a scRNAseq and Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-Seq) experiment of two healthy individuals.
Published: 2021

11. Early IFNβ secretion determines variable downstream IL-12p70 responses upon TLR4 activation

Author: Celine Posseme, Alba Llibre, Bruno Charbit, Vincent Bondet, Vincent Rouilly, Violaine Saint-André, Jeremy Boussier, Jacob Bergstedt, Nikaïa Smith, Liam Townsend, Jamie A. Sugrue, Clíona Ní Cheallaigh, Niall Conlon, Maxime Rotival, Michael S. Kobor, Estelle Mottez, Stanislas Pol, Etienne Patin, Matthew L. Albert, Lluis Quintana-Murci, Darragh Duffy, Laurent Abel, Andres Alcover, Hugues Aschard, Philippe Bousso, Nollaig Bourke, Petter Brodin, Pierre Bruhns, Nadine Cerf-Bensussan, Ana Cumano, Caroline Demangel, null Christophe d’Enfert, Ludovic Deriano, Marie-Agnès Dillies, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay, Ivo Gomperts-Boneca, Milena Hasan, Magnus Fontes, Gunilla Karlsson Hedestam, Serge Hercberg, Molly A. Ingersoll, Rose Anne Kenny, Olivier Lantz, Mickael Ménager, Frédérique Michel, Hugo Mouquet, Cliona O'Farrelly, Sandra Pellegrini, Antonio Rausell, Frédéric Rieux-Laucat, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Frédéric Tangy, Antoine Toubert, Mathilde Touvier, Marie-Noëlle Ungeheuer, Christophe Zimmer, Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Ecole Doctorale Frontiere de l’Innovation en Recherche et Education (ED 474 FIRE), Université Paris Cité (UPCité)-Université Paris sciences et lettres (PSL), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Datactix, Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), St James’s Hospital [Dublin, Ireland], Trinity College Dublin, University of British Columbia [Vancouver], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), HIBIO [South San Francisco], Collège de France - Chaire Génomique humaine et évolution, Collège de France (CdF (institution)), This study was funded with support from the French Governments Investissement dAvenir Program, Laboratoire Excellence Milieu Interieur Grant ANR-10-LABX-69-01 and by an Agence National de Recherche foundation grant (CE17001002)., The Milieu Intérieur Consortium is composed of the following team leaders: Laurent Abel (Hôpital Necker), Andres Alcover, Hugues Aschard, Philippe Bousso, Nollaig Bourke (Trinity College Dublin), Petter Brodin (Karolinska Institutet), Pierre Bruhns, Nadine Cerf-Bensussan (INSERM UMR 1163 – Institut Imagine), Ana Cumano, Caroline Demangel, Christophe d’Enfert, Ludovic Deriano, Marie-Agnès Dillies, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay (EPFL, Lausanne), Ivo Gomperts-Boneca, Milena Hasan, Magnus Fontes (Institut Roche), Gunilla Karlsson Hedestam (Karolinska Institutet), Serge Hercberg (Université Paris 13), Molly Ingersoll, Rose Anne Kenny (Trinity College Dublin), Olivier Lantz (Institut Curie), Frédérique Michel, Hugo Mouquet, Cliona O'Farrelly (Trinity College Dublin), Etienne Patin, Sandra Pellegrini, Stanislas Pol (Hôpital Côchin), Antonio Rausell (INSERM UMR 1163 – Institut Imagine), Frédéric Rieux-Laucat (INSERM UMR 1163 – Institut Imagine), Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Frédéric Tangy, Antoine Toubert (Hôpital Saint-Louis), Mathilde Touvier (Université Paris 13), Marie-Noëlle Ungeheuer, Christophe Zimmer, Matthew L. Albert (In Sitro), Darragh Duffy, Lluis Quintana-Murci, ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), ANR-20-CE17-0010,ELECTRO,Inhibition de l'Exchange Protein directly activated by cAMP -1 pour traiter la Fibrillation Atrial(2020), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute-University of British Columbia (UBC), University of Cape Town, Département d'hépatologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Insitro [San Francisco], St James's University Hospital, Leeds Teaching Hospitals NHS Trust, University of British Columbia (UBC), This study was funded with support from the French Government’s Investissement d’Avenir Program, Laboratoire d’Excellence 'Milieu Intérieur' grant ANR-10-LABX-69-01, and by an Agence National de Recherche Foundation grant (CE17001002). We thank the UTechS CB of the Center for Translational Research, Institut Pasteur for supporting data generation, Pierre-Henri Commere for help with flow cytometry sorting, Aurelie Bisiaux for flow cytometry advice, and Dr. Molly Ingersoll for scientific advice and critical reading of the manuscript. D.D. thanks Immunoqure for provision of the mAbs under an MTA for the Simoa IFNα assay. We thank the STTAR-Bioresource of TCD-SJH-TUH COVID-19 bioresource, which supported collection of COVID-19 patient samples, and the 'URGENCE COVID-19' fundraising campaign of the Institut Pasteur (CoVarImm and Steroid Response) for supporting data generation of COVID-19 samples. N.S. is a recipient of the Pasteur-Roux-Cantarini Fellowship. N.C. and C.N.C. are part funded by a Science Foundation Ireland (SFI) grant, grant code 20/SPP/3685. L.T. is supported by the Irish Clinical Academic Training (ICAT) Program, supported by the Wellcome Trust and the Health Research Board (grant number 203930/B/16/Z), the Health Service Executive, National Doctors Training and Planning, and the Health and Social Care, Research and Development Division, Northern Ireland., Milieu Intérieur Consortium: Laurent Abel, Andres Alcover, Hugues Aschard, Philippe Bousso, Nollaig Bourke, Petter Brodin, Pierre Bruhns, Nadine Cerf-Bensussan, Ana Cumano, Caroline Demangel, Christophe d'Enfert, Ludovic Deriano, Marie-Agnès Dillies, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay, Ivo Gomperts-Boneca, Milena Hasan, Magnus Fontes, Gunilla Karlsson Hedestam, Serge Hercberg, Molly A Ingersoll, Rose Anne Kenny, Olivier Lantz, Mickael Ménager, Frédérique Michel, Hugo Mouquet, Cliona O'Farrelly, Etienne Patin, Sandra Pellegrini, Stanislas Pol, Antonio Rausell, Frédéric Rieux-Laucat, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Frédéric Tangy, Antoine Toubert, Mathilde Touvier, Marie-Noëlle Ungeheuer, Christophe Zimmer, Matthew L Albert, Darragh Duffy, Lluis Quintana-Murci, and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)
Subjects: Lipopolysaccharides, Proteomics, History, Polymers and Plastics, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Disease, systems immunology, Biology, General Biochemistry, Genetics and Molecular Biology, Industrial and Manufacturing Engineering, Immune system, medicine, Humans, Secretion, Epigenetics, Business and International Management, Epigenomics, TLR4 immune responses, Systems immunology, SARS-CoV-2, COVID-19, CP: Immunology, Interferon-beta, Interleukin-12, Toll-Like Receptor 4, Cytokine, IL-12p70, type I interferons, Immunology, TLR4, Cytokine variability, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines
Abstract: International audience; The interleukin-12 (IL-12) family comprises the only heterodimeric cytokines mediating diverse functional effects. We previously reported a striking bimodal IL-12p70 response to lipopolysaccharide (LPS) stimulation in healthy donors. Herein, we demonstrate that interferon β (IFNβ) is a major upstream determinant of IL-12p70 production, which is also associated with numbers and activation of circulating monocytes. Integrative modeling of proteomic, genetic, epigenomic, and cellular data confirms IFNβ as key for LPS-induced IL-12p70 and allowed us to compare the relative effects of each of these parameters on variable cytokine responses. Clinical relevance of our findings is supported by reduced IFNβ-IL-12p70 responses in patients hospitalized with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or chronically infected with hepatitis C (HCV). Importantly, these responses are resolved after viral clearance. Our systems immunology approach defines a better understanding of IL-12p70 and IFNβ in healthy and infected persons, providing insights into how common genetic and epigenetic variation may impact immune responses to bacterial infection.
Published: 2021

12. Distinct systemic and mucosal immune responses to SARS-CoV-2

Author: Ludivine Grzelak, Bruno Charbit, Vincent Bondet, Hélène Péré, Hugo Mouquet, Cyril Planchais, Darragh Duffy, Benjamin Terrier, Vincent Rouilly, Sarah H. Merkling, Nader Yatim, Pedro Gonçalves, Maxime Beretta, Timothée Bruel, Frederic Rieux-Leucat, Nikaïa Smith, Solen Kernéis, Jérôme Hadjadj, James P. Di Santo, Olivier Schwartz, Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris], Immunité Innée - Innate Immunity, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), Immunologie humorale - Humoral Immunology, Datactix, Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Department of Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, Assistance Publique Hôpitaux de Paris-Centre (APHP-CUP), Université de Paris, Paris, France, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Interactions Virus-Insectes - Insect-Virus Interactions (IVI), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Epidémiologie et modélisation de la résistance aux antimicrobiens - Epidemiology and modelling of bacterial escape to antimicrobials (EMAE), This study was supported by an Institut Pasteur Covid-19 research grant and by a grant (CoVarImm) from the Agence National de la Recherche (ANR-flash Covid19) awarded to DD and JPD, and by the Laboratoire d’Excellence ‘‘Milieu Intérieur' (grant no. ANR-10-LABX-69-01) and the Fonds IMMUNOV, for Innovation in Immunopathology. NS is a recipient of the Pasteur-Roux-Cantarini Fellowship. We thank the UTechS CB of the Center for Translational Research, Institut Pasteur for supporting Luminex and Simoa analysis. We thank Laurence Motreff and Laurence Ma, Biomics Platform, C2RT, Institut Pasteur, Paris, France, supported by France Génomique (ANR-10-INBS-09-09), IBISA and the Illumina COVID-19 Projects’ offer for microbial sequencing., ANR-20-COVI-0053,CoVarImm,Variation de la réponse immune systémique et muqueuse pendant l'infection par le SRAS-CoV-2 et la convalescence(2020), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord
Subjects: systemic immunity, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Proinflammatory cytokine, 03 medical and health sciences, 0302 clinical medicine, Immune system, Interferon, medicine, Microbiome, 030304 developmental biology, 0303 health sciences, biology, business.industry, Compartmentalization (psychology), cytokines, 3. Good health, Immunology, biology.protein, mucosal immunity, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, business, Covid-19, Viral load, 030217 neurology & neurosurgery, medicine.drug
Abstract: SummaryCoordinated local mucosal and systemic immune responses following SARS-CoV-2 infection protect against COVID-19 pathologies or fail leading to severe clinical outcomes. To understand this process, we performed an integrated analysis of SARS-CoV-2 spike-specific antibodies, cytokines, viral load and 16S bacterial communities in paired nasopharyngeal swabs and plasma samples from a cohort of clinically distinct COVID-19 patients during acute infection. Plasma viral load was associated with systemic inflammatory cytokines that were elevated in severe COVID-19, and also with spike-specific neutralizing antibodies. In contrast, nasopharyngeal viral load correlated with SARS-CoV-2 humoral responses but inversely with interferon responses, the latter associating with protective microbial communities. Potential pathogenic microrganisms, often implicated in secondary respiratory infections, were associated with mucosal inflammation and elevated in severe COVID-19. Our results demonstrate distinct tissue compartmentalization of SARS-CoV-2 immune responses and highlight a role for the nasopharyngeal microbiome in regulating local and systemic immunity that determines COVID-19 clinical outcomes.
Published: 2021

13. Early IFNβ secretion determines variable downstream IL-12p70 responses upon TLR4 activation in health and disease

Author: Vincent Rouilly, Matthew L. Albert, Michael S. Kobor, Jeremy Boussier, Lluis Quintana-Murci, Maxime Rotival, Jacob Bergstedt, Stanislas Pol, Etienne Patin, Estelle Mottez, Alba Llibre, Violaine Saint-André, Nikaïa Smith, Darragh Duffy, Vincent Bondet, Bruno Charbit, Celine Posseme, Thomas J. Scriba, Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris], Ecole Doctorale Frontiere de l’Innovation en Recherche et Education (ED 474 FIRE), Université de Paris (UP)-Université Paris sciences et lettres (PSL), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Datactix, Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Génétique Evolutive Humaine - Human Evolutionary Genetics, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute-University of British Columbia (UBC), University of Cape Town, Département d'hépatologie [CHU Cochin], Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Insitro [San Francisco], Chaire Génomique humaine et évolution, Collège de France (CdF (institution)), This study was funded with support from the French Governments Investissement dAvenir Program, Laboratoire Excellence Milieu Interieur Grant ANR-10-LABX-69-01 and by an Agence National de Recherche foundation grant (CE17001002)., The Milieu Intérieur Consortium is composed of the following team leaders: Laurent Abel (Hôpital Necker), Andres Alcover, Hugues Aschard, Philippe Bousso, Nollaig Bourke (Trinity College Dublin), Petter Brodin (Karolinska Institutet), Pierre Bruhns, Nadine Cerf-Bensussan (INSERM UMR 1163 – Institut Imagine), Ana Cumano, Caroline Demangel, Christophe d’Enfert, Ludovic Deriano, Marie-Agnès Dillies, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay (EPFL, Lausanne), Ivo Gomperts-Boneca, Milena Hasan, Magnus Fontes (Institut Roche), Gunilla Karlsson Hedestam (Karolinska Institutet), Serge Hercberg (Université Paris 13), Molly Ingersoll, Rose Anne Kenny (Trinity College Dublin), Olivier Lantz (Institut Curie), Frédérique Michel, Hugo Mouquet, Cliona O'Farrelly (Trinity College Dublin), Etienne Patin, Sandra Pellegrini, Stanislas Pol (Hôpital Côchin), Antonio Rausell (INSERM UMR 1163 – Institut Imagine), Frédéric Rieux-Laucat (INSERM UMR 1163 – Institut Imagine), Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Frédéric Tangy, Antoine Toubert (Hôpital Saint-Louis), Mathilde Touvier (Université Paris 13), Marie-Noëlle Ungeheuer, Christophe Zimmer, Matthew L. Albert (In Sitro), Darragh Duffy, Lluis Quintana-Murci, ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), and ANR-20-CE17-0010,ELECTRO,Inhibition de l'Exchange Protein directly activated by cAMP -1 pour traiter la Fibrillation Atrial(2020)
Subjects: Systems immunology, 0303 health sciences, Hepatitis C virus, Disease, Biology, medicine.disease_cause, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Immune system, 030220 oncology & carcinogenesis, Immunology, medicine, TLR4, [SDV.IMM]Life Sciences [q-bio]/Immunology, Secretion, Epigenetics, 030304 developmental biology, Epigenomics
Abstract: SummaryThe IL-12 family of cytokines comprises the only heterodimeric cytokines mediating diverse functional effects. We previously observed a bi-modal IL-12p70 response to LPS in healthy donors of the Milieu Interieur cohort. Herein, we demonstrate that IFNβ expression serves as an upstream determinant of variable IL-12p70 production. Integrative modelling of proteomic, genetic, epigenomic and cellular data confirmed IFNβ as key for regulation of LPS induced IL12A and IL-12p70 variability. The clinical relevance was supported by reduced and variable IL-12p70 responses in individuals infected with the hepatitis C virus (HCV), and findings that IFN-based therapy for HCV is more likely to fail in those patients with dysregulated pre-treatment IL-12p70 responses. In sum, our systems immunology approach has defined a better understanding of IL-12p70 and IFNβ in healthy and infected persons, providing insights into how common genetic and epigenetic variation may impact immune responses to bacterial infection in health and disease.
Published: 2020

14. SCHNAPPs - Single Cell sHiNy APPlication(s)

Author: Bernd Jagla, Vincent Rouilly, Michel Pucéat, and Milena Hasan
Subjects: 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Computer science, Expression data, Cell, medicine, Cluster analysis, Gene, Data science, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: MotivationSingle-cell RNA-sequencing (scRNAseq) experiments are becoming a standard tool for bench-scientists to explore the cellular diversity present in all tissues. On one hand, the data produced by scRNASeq is technically complex, with analytical workflows that are still very much an active field of bioinformatics research, and on the other hand, a wealth of biological background knowledge is often needed to guide the investigation. Therefore, there is an increasing need to develop applications geared towards bench-scientists to help them abstract the technical challenges of the analysis, so that they can focus on the Science at play. It is also expected that such applications should support closer collaboration between bioinformaticians and bench-scientists by providing reproducible science tools.ResultsWe present SCHNAPPs, a computer program designed to enable bench-scientists to autonomously explore and interpret single cell RNA-seq expression data and associated annotations. The Shiny-based application allows selecting genes and cells of interest, performing quality control, normalization, clustering, and differential expression analyses, applying standard workflows from Seurat (Stuart et al., 2019) or Scran (Lun et al., 2016) packages, and most of the common visualizations. An R-markdown report can be generated that tracks the modifications, and selected visualizations facilitating communication and reproducibility between bench-scientist and bioinformatician. The modular design of the tool allows to easily integrate new visualizations and analyses by bioinformaticians. We still recommend that a data analysis specialist oversees the analysis and interpretation.AvailabilityThe SCHNAPPs application, docker file, and documentation are available on GitHub: https://c3bi-pasteur-fr.github.io/UTechSCB-SCHNAPPs; Example contribution are available at the following GitHub site: https://github.com/baj12/SCHNAPPsContributions.
Published: 2020

15. 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

16. Immune profiling in M. tuberculosis infection enables stratification of patients with active disease

Author: Alba Llibre, Simbarashe Mabwe, Matthew L. Albert, Nicole Bilek, Elizabeth Filander, Mark Hatherill, Humphrey Mulenga, Stéphanie Thomas, Elisa Nemes, Lungisa Jaxa, Vincent Rouilly, Hadn Africa, Munyaradzi Musvosvi, Thomas J. Scriba, Bruno Charbit, and Darragh Duffy
Subjects: Innate immune system, Tuberculosis, biology, business.industry, Stimulation, Disease, biology.organism_classification, medicine.disease, bacterial infections and mycoses, Asymptomatic, Mycobacterium tuberculosis, Antigen, Immunology, medicine, medicine.symptom, business, Whole blood
Abstract: Tuberculosis (TB) is caused byMycobacterium tuberculosis(Mtb) infection and is a major public health problem with an estimated 1.7 billion persons infected worldwide. Clinical challenges in TB include the lack of a blood-based test for active disease, and the absence of prognostic biomarkers for early treatment response. Current blood based tests, such as QuantiFERON-TB Gold (QFT), are based on an IFNγ readout followingMtbantigen stimulation. However, they do not distinguish active TB disease from asymptomaticMtbinfection. We hypothesized that the use of TruCulture, an improved immunomonitoring method for whole blood collection and immune stimulation, could improve the discrimination of active disease from latentMtbinfection. To test our hypothesis, we stimulated whole blood from active TB patients (before and after successful treatment), comparing them to asymptomatic latently infected individuals.Mtb-specific antigens (ESAT-6, CFP-10, TB7.7) and live bacillus Calmette-Guerin (BCG) were used for TruCulture stimulation conditions, with direct comparison to QFT. Protein analyses were performed on the culture supernatants using ELISA and Luminex multi-analyte profiling. TruCulture showed an ability to discriminate active TB cases from latent controls (p < 0.0001, AUC = 0.81, 95% CI: 0.69-0.93) as compared to QFT (p = 0.47 AUC = 0.56, 95% CI: 0.40-0.72), based on an IFNγ readout afterMtbantigen stimulation. The stratification of the two groups could be further improved by using theMtbAg/BCG IFNγ ratio response (p < 0.0001, AUC = 0.918, 95% CI: 0.84-0.98). We also identified additional cytokines that distinguished latent infection from TB disease; and show that the primary differences between the TruCulture and QFT systems were a result of higher levels of non-specific innate immune activation in QFT tubes, due to the lack of a buffering solution in the latter. We conclude that TruCulture offers a next-generation solution for whole blood stimulation and immunomonitoring with the possibility to discriminate active and latently infected persons.
Published: 2019
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17. Publisher Correction: Natural variation in the parameters of innate immune cells is preferentially driven by genetic factors

Author: Vincent Rouilly, Cherie Green, Lluis Quintana-Murci, Julie Hunkapiller, Isabelle Peguillet, Magnus Fontes, Jacob Bergstedt, Alejandra Urrutia, Claire Leloup, Benoit Beitz, Friederike Jönsson, Darragh Duffy, Stéphanie Thomas, François Huetz, Lars Rogge, Cécile Alanio, Matthew L. Albert, Petar Scepanovic, Olivier Lantz, Barbara Piasecka, Yoong Wearn Lim, Jacques Fellay, Hélène Quach, Christian Hammer, Milena Hasan, Etienne Patin, Magge Zepeda, Valentina Libri, and James P. Di Santo
Subjects: 0301 basic medicine, Innate immune system, Immunology, Computational biology, Biology, Natural variation, InformationSystems_GENERAL, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Correct name, Immunology and Allergy
Abstract: In the version of this article initially published, the name of one author was incorrect (James P. Santo). The correct name is James P. Di Santo. The error has been corrected in the HTML and PDF versions of the article.
Published: 2018

18. 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

19. 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

20. Engineering a synthetic molecular oscillator based on the Lotka-Volterra dynamic.

Author: Christin Sander, Farah Vohra, John Chattaway, Tom Hinson, John Sy, Jiongjun Bai, Jonathan Wells, Deepti Aswani, Vincent Rouilly, Chueh-Loo Poh, Matthieu Bultelle, Kirsten Jensen, David Mann, Paul S. Freemont, and Richard Kitney
Published: 2007
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21. Registry of BioBricks models using CellML.

Author: Vincent Rouilly, Barry Canton, Poul M. F. Nielsen, and Richard Kitney
Published: 2007
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22. Automated flow cytometric analysis across large numbers of samples and cell types

Author: Lluis Quintana-Murci, Valentina Libri, Bernard Chalmond, Xiaoyi Chen, Vincent Rouilly, Benoit Beitz, Alejandra Urrutia, Matthew L. Albert, Lars Rogge, Milena Hasan, Etienne Patin, Darragh Duffy, Benno Schwikowski, Biologie systémique - Systems Biology, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Analyse, Géométrie et Modélisation (AGM - UMR 8088), CY Cergy Paris Université (CY)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie Humaine (CIH), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunobiologie des Cellules Dendritiques, Immunorégulation, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre de Mathématiques et de Leurs Applications (CMLA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Université de Cergy Pontoise (UCP), Université Paris-Seine, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Non Linéaire de Nice Sophia-Antipolis (INLN), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), The Milieu Intérieur Consortium is composed of the following team leaders: Laurent Abel (Hôpital Necker), Andres Alcover, Philippe Bousso, Pierre Bruhns, Ana Cumano, Marc Daëron, Cécile Delval, Caroline Demangel, Ludovic Deriano, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Odile Gelpi, Antonio Freitas, Ivo Gomperts-Boneca, Serge Hercberg (Université Paris 13), Olivier Lantz (Institut Curie), Claude Leclerc, Hugo Mouquet, Sandra Pellegrini, Stanislas Pol (Hôpital Côchin), Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Vassili Soumelis (Institut Curie), Frédéric Tangy, Eric Tartour (Hôpital Européen George Pompidou), Antoine Toubert (Hôpital Saint-Louis), Marie-Noëlle Ungeheuer, Lluis Quintana-Murci2, Matthew L. Albert3.Additional information can be found at: http://www.pasteur.fr/labex/milieu-interieur., Kop, Marie-Luce, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)
Subjects: Multidimensional analysis, [SDV.IMM] Life Sciences [q-bio]/Immunology, Neutrophils, Computer science, T-Lymphocytes, Pipeline (computing), Statistics as Topic, Immunology, Flow cytometry, Gating, Bioinformatics, Monocytes, Automation, T-Lymphocyte Subsets, Bayesian information criterion, Cluster Analysis, Humans, Immunology and Allergy, Population-based cohort, Cluster analysis, Automation, Laboratory, B-Lymphocytes, business.industry, Bayes Theorem, Dendritic Cells, Reference Standards, Mixture model, Standardization, Killer Cells, Natural, Identification (information), ComputingMethodologies_PATTERNRECOGNITION, [SDV.IMM]Life Sciences [q-bio]/Immunology, Algorithms, Biological system, business, Software
Abstract: International audience; Multi-parametric flow cytometry is a key technology for characterization of immune cell phenotypes. However, robust high-dimensional post-analytic strategies for automated data analysis in large numbers of donors are still lacking. Here, we report a computational pipeline, called FlowGM, which minimizes operator input, is insensitive to compensation settings, and can be adapted to different analytic panels. A Gaussian Mixture Model (GMM)-based approach was utilized for initial clustering, with the number of clusters determined using Bayesian Information Criterion. Meta-clustering in a reference donor permitted automated identification of 24 cell types across four panels. Cluster labels were integrated into FCS files, thus permitting comparisons to manual gating. Cell numbers and coefficient of variation (CV) were similar between FlowGM and conventional gating for lymphocyte populations, but notably FlowGM provided improved discrimination of "hard-to-gate" monocyte and dendritic cell (DC) subsets. FlowGM thus provides rapid high-dimensional analysis of cell phenotypes and is amenable to cohort studies.
Published: 2015

23. Standardized whole blood stimulation improves immunomonitoring of induced immune responses in multi-center study

Author: Alain Savenay, Matthew L. Albert, Delphine Louis, Manfred Schmolz, Nina Salabert-Le Guen, Olivier Lantz, Régis Josien, Darragh Duffy, Françoise Mascart, Antoine Toubert, Marie Noelle Ungeheuer, Vincent Rouilly, Raouf Djebali, Lydia Redjah, José J.G. Ruiz de Morales, Catherine Ottone, Véronique Corbière, Eva Martínez-Cáceres, Cécile Braudeau, Samuel S.T. LaBrie, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle (CRT), Institut Pasteur [Paris], Laboratoire d’Immunologie, Centre d’Immunomonitorage Nantes Atlantique (CIMNA), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), 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), laboratoire de vaccinologie et immunité mucosale, Université Libre de Bruxelles [Bruxelles] (ULB), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Myriad RBM, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospital Universitari Germans Trias I Pujol, Immunobiology Clinic, Hôpital Erasme, Complejo Asistencial Universitario de León, Alloimmunité-Autoimmunité-Transplantation (A2T), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), HOT Screen GmbH, Genentech, Inc. [San Francisco], TruCulture tubes, stimuli, and protein Luminex XMAP analysis were provided by Myriad RBM, Inc (Austin, USA) and TruCulture tubes were manufactured at HOT Screen (Reutlingen, Germany). Donor recruitment costs were covered by each participating FOCIS center of excellence. Author contributions: DD, VR, VC, SL, OL, EMC, RP, MS, AT & MLA designed the study. CB, RD, MNU, DL, FM, JGRM, CO, LR, AS performed experiments. DD, VR, & MLA performed analysis and wrote the paper. All authors reviewed the manuscript., 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), Université libre de Bruxelles (ULB), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche Translationnelle ( CRT ), Centre Hospitalier Universitaire de Nantes, Centre de Recherche en Transplantation et Immunologie ( U1064 Inserm - CRTI - CHU Nantes ), Université de Nantes ( UN ) -Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Université Libre de Bruxelles [Bruxelles] ( ULB ), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources ( ICAReB ), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Curie, Alloimmunité-Autoimmunité-Transplantation ( A2T ), and Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: 0301 basic medicine, Lipopolysaccharides, Whole blood stimulation, CD3 Complex, medicine.medical_treatment, CD8 Antigens, Point-of-Care Systems, Immunology, Stimulation, Blood Donors, Immunologic Tests, Peripheral blood mononuclear cell, Antibodies, Functional immune responses, 03 medical and health sciences, Immune system, medicine, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, Humans, Whole blood, biology, business.industry, Immunotherapy, Multi-center clinical studies, 3. Good health, Vaccination, Immunomonitoring, 030104 developmental biology, Gene Expression Regulation, PBMCs, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, Antibody, business, Biomarkers
Abstract: Functional immune responses are increasingly important for clinical studies, providing in depth biomarker information to assess immunotherapy or vaccination. Incorporating functional immune assays into routine clinical practice has remained limited due to challenges in standardizing sample preparation. We recently described the use of a whole blood syringe-based system, TruCulture (R), which permits point-of-care standardized immune stimulation. Here, we report on a multi-center clinical study in seven FOCIS Centers of Excellence to directly compare TruCulture to conventional PBMC methods. Whole blood and PBMC5 from healthy donors were exposed to LPS, anti-CD3 anti-CD28 antibodies, or media alone. 55 protein analytes were analyzed centrally by Luminex multi-analyte profiling in a CLIA-certified laboratory. TruCulture responses showed greater reproducibility and improved the statistical power for monitoring differential immune response activation. The use of TruCulture addresses a major unmet need through a robust and flexible method for immunomonitoring that can be reproducibly applied in multi-center clinical studies. One sentence summary: A multi-center study revealed greater reproducibility from whole blood stimulation systems as compared to PBMC stimulation for studying induced immune responses. (C) 2017 Published by Elsevier Inc.
Published: 2017

24. Simultaneous analysis of large-scale RNAi screens for pathogen entry

Author: Peter Bühlmann, Bernd Rinn, Vincent Rouilly, Shyan Huey Low, Christoph Dehio, Matthias C. Truttmann, Pauli Rämö, Niko Beerenwinkel, Wolf-Dietrich Hardt, Gabriel Studer, Mario Emmenlauer, Alain Casanova, Christian von Mering, Jason Mercer, Eva Pujadas, Juliane Siebourg-Polster, Cécile Arrieumerlou, Houchaima Ben-Tekaya, Michael Podvinec, Javier Pizarro-Cerdá, Artur Yakimovich, Andreas Kaufmann, Michael Stebler, Raquel Conde-Álvarez, Bettina Cardel, Simone Eicher, Fabian Schmich, Ari Helenius, Anna Drewek, Peter Z. Kunszt, Christoph Kasper, Lucas Pelkmans, Simone Muntwiler, Ewa Szczurek, Gabor Csucs, Pascale Cossart, Andreas Kühbacher, Daria Mudrak, Berend Snijder, Saskia Kreibich, Urs F. Greber, Andreas Vonderheit, University of Basel (Unibas), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Université Paris Descartes - Paris 5 (UPD5), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Universität Zürich [Zürich] = University of Zurich (UZH), Universidad de Navarra [Pamplona] (UNAV), Interactions Bactéries-Cellules (UIBC), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Biochemistry, Vilnius University [Vilnius], Institut National de la Recherche Agronomique (INRA), SystemsX Ch, SyBIT, Partenaires INRAE, Inst Mol Biol, Swiss Initiative for Systems Biology [51RT0_126008, 51RTP0_151029], Swiss National Science Foundation (SNSF) [31003A-132979], ERC advanced grant [340330, 233348], ANR [MIE-2009-SignRupVac], Fondation Le Roch and Fondation Jeantet, Pasteur-Paris University International Doctoral Program/Institut Carnot Maladies Infectieuses, ETH Zurich Postdoctoral Fellowship Program, Marie Curie Actions for People COFUND program [FEL-13 12-1], SystemsX.ch, Swiss initiative in systems biology, under IPhd [2009/025], International PhD Program 'Fellowships for Excellence' of the Biozentrum, grant SystemsX iPhD, grant Novartis: Stiftung fur Medizinisch-Biologische Forschung, University of Zurich: Bauten und Investitionen, SNSF [31003A_141222/1], iPhD fellowship [SXPHIO_142001/1], University of Zurich, Dehio, Christoph, and Université de Lausanne (UNIL)
Subjects: Small interfering RNA, base de séquences, hit detection, [SDV]Life Sciences [q-bio], arn i, Genomics, Computational biology, Biology, Proteomics, Cell Line, 1311 Genetics, RNA interference, High-Throughput Screening Assays, Genetics, Humans, RNA, Small Interfering, Gene Library, Effector, high-throughput high-content RNAi screening, Scale (chemistry), screening, Reproducibility of Results, pathogen entry, linear mixed model, 10124 Institute of Molecular Life Sciences, ROC Curve, Host-Pathogen Interactions, High-throughput high-content RNAi screening, Pathogen entry, Linear mixed model, Hit detection, 1305 Biotechnology, 570 Life sciences, biology, RNA Interference, DNA microarray, Biotechnology, Research Article
Abstract: Background Large-scale RNAi screening has become an important technology for identifying genes involved in biological processes of interest. However, the quality of large-scale RNAi screening is often deteriorated by off-targets effects. In order to find statistically significant effector genes for pathogen entry, we systematically analyzed entry pathways in human host cells for eight pathogens using image-based kinome-wide siRNA screens with siRNAs from three vendors. We propose a Parallel Mixed Model (PMM) approach that simultaneously analyzes several non-identical screens performed with the same RNAi libraries. Results We show that PMM gains statistical power for hit detection due to parallel screening. PMM allows incorporating siRNA weights that can be assigned according to available information on RNAi quality. Moreover, PMM is able to estimate a sharedness score that can be used to focus follow-up efforts on generic or specific gene regulators. By fitting a PMM model to our data, we found several novel hit genes for most of the pathogens studied. Conclusions Our results show parallel RNAi screening can improve the results of individual screens. This is currently particularly interesting when large-scale parallel datasets are becoming more and more publicly available. Our comprehensive siRNA dataset provides a public, freely available resource for further statistical and biological analyses in the high-content, high-throughput siRNA screening field., BMC Genomics, 15, ISSN:1471-2164
Published: 2014

25. 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

26. Engineering a molecular predation oscillator

Author: Richard I. Kitney, Paul S. Freemont, and Vincent Rouilly
Subjects: Amplitude, Basis (linear algebra), Computer science, Bioengineering, Control engineering, System requirements specification, Context (language use), Cell Biology, Molecular Biology, Stability (probability), Simulation, Biotechnology, Term (time)
Abstract: The paper addresses the problem of designing and building a stable molecular based oscillator which can be controlled in terms of both amplitude and frequency. A study of previous oscillators of this type showed that they are inherently unstable. To overcome this problem a design was chosen which is based on Lotka–Voltera dynamics. An important aspect of the work was the use of what we term the Engineering Cycle; that is, the cycle of system specification, design, modelling, implementation, and testing and validation. The Lotka–Voltera dynamic, in the context of a predation oscillator, amounts to a predator–prey approach. This is the basis of the oscillator design. The oscillator was designed and detailed modelling undertaken to establish the modes of the dynamic; how it could be tuned for stability; and how to control its amplitude and frequency. The biological implementation of the design was undertaken using a number of BioBricks from the MIT registry (http://parts.mit.edu/registry/index.php/Main_Page), together with a number of parts which we designed and built.
Published: 2007

27. iBRAIN2: automated analysis and data handling for RNAi screens

Author: Vincent, Rouilly, Eva, Pujadas, Béla, Hullár, Csaba, Balázs, Peter, Kunszt, and Michael, Podvinec
Subjects: Internet, Sequence Analysis, RNA, Databases, Genetic, Database Management Systems, Information Storage and Retrieval, RNA Interference, Algorithms, Software
Abstract: We report on the implementation of a software suite dedicated to the management and analysis of large scale RNAi High Content Screening (HCS). We describe the requirements identified amongst our different users, the supported data flow, and the implemented software. Our system is already supporting productively three different laboratories operating in distinct IT infrastructures. The system was already used to analyze hundreds of RNAi HCS plates.
Published: 2012

28. Opportunities for microfluidic technologies in synthetic biology

Author: James Chappell, Xize Niu, Andrew J. deMello, Vincent Rouilly, Shelly Gulati, Paul S. Freemont, Richard I. Kitney, and Joshua B. Edel
Subjects: Systems biology, Green Fluorescent Proteins, Microfluidics, Biomedical Engineering, Biophysics, Bioengineering, Nanotechnology, Biology, Models, Biological, Polymerase Chain Reaction, Biochemistry, Biomaterials, Synthetic biology, Humans, Hardware_ARITHMETICANDLOGICSTRUCTURES, Miniaturization, business.industry, Gene Expression Profiling, Systems Biology, Computational Biology, DNA-Directed RNA Polymerases, Equipment Design, Articles, Microfluidic Analytical Techniques, Biotechnology, Genetic Engineering, Engineering principles, business
Abstract: We introduce microfluidics technologies as a key foundational technology for synthetic biology experimentation. Recent advances in the field of microfluidics are reviewed and the potential of such a technological platform to support the rapid development of synthetic biology solutions is discussed.
Published: 2009

29. The Milieu Intérieur study — An integrative approach for study of human immunological variance

Author: Stéphanie Thomas, Vincent Rouilly, Etienne Patin, Cécile Alanio, Annick Dubois, Cécile Delval, Louis-Guillaume Marquier, Nicolas Fauchoux, Seloua Sayegrih, Muriel Vray, Darragh Duffy, Lluis Quintana-Murci, Matthew L. Albert, Laurent Abel, Andres Alcover, Philippe Bousso, Pierre Bruhns, Ana Cumano, Marc Daëron, Caroline Demangel, Ludovic Deriano, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Antonio Freitas, Odile Gelpi, Ivo Gomperts-Boneca, Serge Hercberg, Olivier Lantz, Claude Leclerc, Hugo Mouquet, 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, Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Pôle Intégré de Recherche Clinique (PIRC), Institut Pasteur [Paris], Biotrial, Biotrial, Rennes, France, 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 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). We acknowledge the advice of the 'healthy donor' working group that helped us to define the inclusion/exclusion criteria: Laurent Abel, François Aubin, Raphaëlle Bourdet-Sicard, Ingrid Callies, Miguel Fenoy, Bridget Holmes, Laurence Mathivet, Cédric Ménager, Stéphane Reynier, Manfred Schmoltz, Muriel Vray). Scientific advisory board members that supported the trial design discussions included: Hyam Levitsky, Philip Greenberg, John Marioni, Jonathan Braun, Adrian Hayday and Thomas Joos. We also thank Dusko Ehrlich and Joël Doré for advice on stool sample collection procedures. We would like to acknowledge all the Biotrial team of doctors, nurses, technicians and project managers for their expertise and professionalism. We also thank the donors for their contribution to the study., Consortium 'Milieu Intérieur' (34 collaborateurs) : Abel L, Alcover A, Bousso P, Bruhns P, Cumano A, Daëron M, Delval C, Demangel C, Deriano L, Di Santo J, Dromer F, Eberl G, Enninga J, Freitas A, Gelpi O, 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] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), 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), RIBIERRE, Helene, and Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID
Subjects: Gerontology, Adult, Male, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Cohort design, Population, Immunology, Disease, Immune phenotypes, Bioinformatics, Cohort Studies, Young Adult, Sex Factors, Risk Factors, Epidemiology, Medicine, SNP, Immunology and Allergy, Humans, Milieu intérieur, education, Aged, education.field_of_study, business.industry, Smoking, Age Factors, CMV, Variance (accounting), Healthy donor, Middle Aged, Baseline serologic data, Metabolic syndrome, 3. Good health, Cross-Sectional Studies, Socioeconomic Factors, Immune System, Cytomegalovirus Infections, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Sample collection, France, business, Cohort study
Abstract: International audience; The Milieu Intérieur Consortium has established a 1000-person healthy population-based study (stratified according to sex and age), creating an unparalleled opportunity for assessing the determinants of human immunologic variance. Herein, we define the criteria utilized for participant enrollment, and highlight the key data that were collected for correlative studies. In this report, we analyzed biological correlates of sex, age, smoking-habits, metabolic score and CMV infection. We characterized and identified unique risk factors among healthy donors, as compared to studies that have focused on the general population or disease cohorts. Finally, we highlight sex-bias in the thresholds used for metabolic score determination and recommend a deeper examination of current guidelines. In sum, our clinical design, standardized sample collection strategies, and epidemiological data analyses have established the foundation for defining variability within human immune responses.
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30. Interleukin-10 induces interferon-γ-dependent emergency myelopoiesis

Author: Ana, Cardoso, Ana Catarina, Martins, Ana Raquel, Maceiras, Wei, Liu, Isabel, Castro, António G, Castro, António, Bandeira, James P, Di Santo, Ana, Cumano, Yan, Li, Paulo, Vieira, Margarida, Saraiva, Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto = University of Porto, Instituto de Biologia Molecular e Celular - institute for molecular and cell biology [Porto, Portugal] (IBMC), Lymphocytes et Immunité - Lymphocytes and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Medical School (University of Nanjing), Nanjing University (NJU), University of Minho [Braga], Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Immunité Innée - Innate Immunity, A. Cardoso (SFRH/BD/84704/2012) and A.C.M. (SFRH/BD/136800/2018) were supported by the Portuguese Foundation for Science and Technology (FCT) through PhD grants.This study was partially supported by grants from the National Key Research and Development Program of China (2019YFA0802900), National Natural Science Foundation of China (32070942), and Fundamental Research Funds for the Central Universities.The M.S. lab was financed by a FCT-ANR grant (MyeloTEN-FCTANR/ BIM-MEC/0007/2013). We acknowledge the GenomePT project (POCI-01-0145-FEDER-022184), supported by COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation (POCI), Lisboa Portugal Regional Operational Programme (Lisboa2020), Algarve Portugal Regional Operational Programme (CRESC Algarve2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and by FCT.This work was funded by National Funds through FCT, I.P., under the project UIDB/04293/2020, and backed by the COST Action BM1404 European Network of Investigators Triggering Exploratory Research on Myeloid Regulatory Cells (http://www.mye-euniter.eu), which is supported by the Horizon 2020—EU Framework Program Research and Innovation Programme. M.S. is funded by FCT through Estímulo Individual ao Emprego Científico.A. Cumano and P.V. were financed by ANR Twothyme and by REVIVE (Investissement d’Avenir, ANR-10-LABX-73). A.B., A. Cumano, and P.V. were also financed by the Institut Pasteur, INSERM, and ANR (project MYELOTEN, ANR-13-ISV1-0003-01)., We thank Vincent Rouilly for statistical advice and Werner Müller (University of Manchester), Rui Appelberg (i3S), and Bruno Silva-Santos (iMM) for providing the IL-10Rα-, IFN-γ-, and TCRγδ-deficient animals, respectively. We thank Anne O’Garra for helpful discussions and for critical reading of the manuscript. We also thank Delfim Duarte and Maria José Teles for helpful discussions and for helping with the hemogram quantification. We thank Caetano Reis e Sousa for help with the preparation of the graphical abstract. We thank the support of the personnel in the animal facilities, the i3S scientific platforms Translational Cytometry (TraCy), and Histology and Electron Microscopy (HEMS). HEMS is a member of the national infrastructure PPBI (Portuguese Platform of Bioimaging, PPBI-POCI-01-0145-FEDER-022122)., ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), ANR-13-ISV1-0003,MYELOTEN,DEREGULATION DE L'HEMATOPOIESE PAR LA SUREXPRESSION DE L'INTERLEUKINE-10 : IMPLICATIONS DANS LE DEVELOPPEMENT DE PATHOLOGIES HEMATOLOGIQUES(2013), European Project, Vougny, Marie-Christine, Laboratoires d'excellence - Stem Cells in Regenerative Biology and Medicine - - REVIVE2010 - ANR-10-LABX-0073 - LABX - VALID, Blanc – Accords bilatéraux 2013 - DEREGULATION DE L'HEMATOPOIESE PAR LA SUREXPRESSION DE L'INTERLEUKINE-10 : IMPLICATIONS DANS LE DEVELOPPEMENT DE PATHOLOGIES HEMATOLOGIQUES - - MYELOTEN2013 - ANR-13-ISV1-0003 - Blanc – Accords bilatéraux 2013 - VALID, COST Action BM1404 MyeEUNITER - INCOMING, Universidade do Porto, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: CD4-Positive T-Lymphocytes, Mice, Knockout, Myelopoiesis, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cells, emergency myelopoiesis, CD8-Positive T-Lymphocytes, Interleukin-10, Interferon-gamma, Mice, IL-10, Animals, [SDV.IMM]Life Sciences [q-bio]/Immunology, IFN-γ, Myeloid Progenitor Cells
Abstract: International audience; In emergency myelopoiesis (EM), expansion of the myeloid progenitor compartment and increased myeloid cell production are observed and often mediated by the pro-inflammatory cytokine interferon gamma (IFN-γ). Interleukin-10 (IL-10) inhibits IFN-γ secretion, but paradoxically, its therapeutic administration to humans causes hematologic changes similar to those observed in EM. In this work, we use different in vivo systems, including a humanized immune system mouse model, to show that IL-10 triggers EM, with a significant expansion of the myeloid progenitor compartment and production of myeloid cells. Hematopoietic progenitors display a prominent IFN-γ transcriptional signature, and we show that IFN-γ mediates IL-10-driven EM. We also find that IL-10, unexpectedly, reprograms CD4 and CD8 T cells toward an activation state that includes IFN-γ production by these T cell subsets in vivo. Therefore, in addition to its established anti-inflammatory properties, IL-10 can induce IFN-γ production and EM, opening additional perspectives for the design of IL-10-based immunotherapies.
Published: 2021

31. 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

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31 results on '"Vincent Rouilly"'

1. Defective activation and regulation of type I interferon immunity is associated with increasing COVID-19 severity

2. Tuberculosis alters immune-metabolic pathways resulting in perturbed IL-1 responses

3. Standardized Whole-Blood Transcriptional Profiling Enables the Deconvolution of Complex Induced Immune Responses

4. In situ tumour arrays reveal early environmental control of cancer immunity

5. Tuberculosis alters immune-metabolic pathways resulting in perturbed IL-1 responses

6. iBRAIN2: Automated analysis and data handling for RNAi screens.

7. Defective type I interferon immunity is associated with increasing COVID-19 severity

8. Immune Profiling Enables Stratification of Patients With Active Tuberculosis Disease or Mycobacteriu m tuberculosis Infection

9. Polygenic risk for skin autoimmunity impacts immune checkpoint blockade in bladder cancer

10. SCHNAPPs - Single Cell sHiNy APPlication(s)

11. Early IFNβ secretion determines variable downstream IL-12p70 responses upon TLR4 activation

12. Distinct systemic and mucosal immune responses to SARS-CoV-2

13. Early IFNβ secretion determines variable downstream IL-12p70 responses upon TLR4 activation in health and disease

14. SCHNAPPs - Single Cell sHiNy APPlication(s)

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

16. Immune profiling in M. tuberculosis infection enables stratification of patients with active disease

17. Publisher Correction: Natural variation in the parameters of innate immune cells is preferentially driven by genetic factors

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

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

20. Engineering a synthetic molecular oscillator based on the Lotka-Volterra dynamic.

21. Registry of BioBricks models using CellML.

22. Automated flow cytometric analysis across large numbers of samples and cell types

23. Standardized whole blood stimulation improves immunomonitoring of induced immune responses in multi-center study

24. Simultaneous analysis of large-scale RNAi screens for pathogen entry

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

26. Engineering a molecular predation oscillator

27. iBRAIN2: automated analysis and data handling for RNAi screens

28. Opportunities for microfluidic technologies in synthetic biology

29. The Milieu Intérieur study — An integrative approach for study of human immunological variance

30. Interleukin-10 induces interferon-γ-dependent emergency myelopoiesis

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

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31 results on '"Vincent Rouilly"'

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