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2. Study on Infectious Mononucleosis in Munich (IMMUC)

Author

Helmholtz Zentrum München, German Cancer Research Center, Ludwig-Maximilians - University of Munich, Hannover Medical School, University Hospital Freiburg, and German Center for Infection Research

Published
2024

4. Platform Assessing Regimens and Durations In a Global Multisite Consortium for TB (PARADIGM4TB)

Author

Radboud University Medical Center, London School of Hygiene and Tropical Medicine, University of Oxford, Research Center Borstel, Lygature, TASK Applied Science, Vita-Salute San Raffaele University, Helmholtz Zentrum Munchen, KNCV Tuberculosis Foundation, Critical Path Institute, European Lung Foundation, Instituto de Saude Publica da Universidade do Porto, University of Liverpool, Institut de Recherche Pour le Developpment, University of Hamburg-Eppendorf, University of California, San Francisco, TB Alliance, Find, University of Milano, University of St Andrews, Uppsala University, European Respiratory Society, Tuberculosis Network European Trialsgroup, Janssen, LP, Otsuka Pharmaceutical Development & Commercialization, Inc., German Center for Infection Research, LMU University Hospital Munich, University of Cambridge, and GlaxoSmithKline

Published
2024

9. HIV and STIs Clinical Study in Germany

Author

US Military HIV Research Program, United States Army Medical Materiel Development Activity, Federal Ministry of Health, Germany, German Center for Infection Research, and Hendrik Streeck, Prof. Dr. med. Hendrik Streeck

Published
2022

17. A Single Ascending Dose Study of BTZ043

Author

German Center for Infection Research, German Federal Ministry of Education and Research, Hans Knöll Institute (HKI), and Michael Hoelscher, Director

Published
2019

24. Incidences of Infectious Events in a Renal Transplant Cohort of the German Center of Infectious Diseases (DZIF).

Author

Sommerer, Claudia, Schröter, Iris, Gruneberg, Katrin, Schindler, Daniela, Behnisch, Rouven, Morath, Christian, Renders, Lutz, Heemann, Uwe, Schnitzler, Paul, Melk, Anette, Penna, Andrea Della, Nadalin, Silvio, Heeg, Klaus, Meuer, Stefan, Zeier, Martin, Giese, Thomas, and Consortium, for the Transplant Cohort of the German Center for Infection Research (DZIF Transplant Cohort)

Subjects
KIDNEY transplantation, COMMUNICABLE diseases, ESCHERICHIA coli, OPPORTUNISTIC infections, MYCOSES, PNEUMOCYSTIS jiroveci, ENTEROCOCCAL infections
Abstract

Background Infectious complications are a major cause of morbidity and mortality after kidney transplantation. Methods In this transplant cohort study at the German Center of Infectious Diseases (DZIF), we evaluated all infections occurring during the first year after renal transplantation. We assessed microbial etiology, incidence rates, and temporal occurrence of these infections. Results Of 804 renal transplant recipients (65.2% male, 51 ± 14 years), 439 (54.6%) had 972 infections within the first year after transplantation. Almost half of these infections (47.8%) occurred within the first 3 months. Bacteria were responsible for 66.4% (645/972) of all infections, followed by viral (28.9% [281/972]) and fungal (4.7% [46/972]) pathogens. The urinary tract was the most common site of infection (42.4%). Enterococcus was the most frequently isolated bacterium (20.9%), followed by E. coli (17.6%) and Klebsiella (12.5%). E. coli was the leading pathogen in recipients <50 years of age, whereas Enterococcus predominated in older recipients. Resistant bacteria were responsible for at least 1 infection in 9.5% (76/804) of all recipients. Viral infections occurred in 201 recipients (25.0%). Of these, herpes viruses predominated (140/281 [49.8%]), and cytomegalovirus had the highest incidence rate (12.3%). In the 46 fungal infections, Candida albicans (40.8%) was the most commonly isolated. Other fungal opportunistic pathogens, including Aspergillus fumigatus and Pneumocystis , were rare. Conclusions Renal allograft recipients in Germany experience a high burden of infectious complications in the first year after transplantation. Bacteria were the predominating pathogen, followed by opportunistic infections such as cytomegalovirus. Microbial etiology varied between age groups, and resistant bacteria were identified in 10% of recipients. [ABSTRACT FROM AUTHOR]

Published
2022
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25. The transplant cohort of the German center for infection research (DZIF Tx-Cohort): study design and baseline characteristics.

Author

Karch, André, Schindler, Daniela, Kühn-Steven, Andrea, Blaser, Rainer, Kuhn, Klaus A., Sandmann, Lisa, Sommerer, Claudia, Guba, Markus, Heemann, Uwe, Strohäker, Jens, Glöckner, Stephan, Mikolajczyk, Rafael, Busch, Dirk H., Schulz, Thomas F., for the Transplant Cohort of the German Center for Infection Research (DZIF Transplant Cohort) Consortium, Lehmann, Andreas, Ganser, Arnold, Lange, Berit, Maecker-Kolhoff, Britta, and Tönshoff, Burkhard

Subjects
STEM cell transplantation, TRANSPLANTATION of organs, tissues, etc., RESEARCH institutes, EXPERIMENTAL design, STANDARD operating procedure, ARTIFICIAL pancreases, ARTIFICIAL hearts
Abstract

Infectious complications are the major cause of morbidity and mortality after solid organ and stem cell transplantation. To better understand host and environmental factors associated with an increased risk of infection as well as the effect of infections on function and survival of transplanted organs, we established the DZIF Transplant Cohort, a multicentre prospective cohort study within the organizational structure of the German Center for Infection Research. At time of transplantation, heart-, kidney-, lung-, liver-, pancreas- and hematopoetic stem cell- transplanted patients are enrolled into the study. Follow-up visits are scheduled at 3, 6, 9, 12 months after transplantation, and annually thereafter; extracurricular visits are conducted in case of infectious complications. Comprehensive standard operating procedures, web-based data collection and monitoring tools as well as a state of the art biobanking concept for blood, purified PBMCs, urine, and faeces samples ensure high quality of data and biosample collection. By collecting detailed information on immunosuppressive medication, infectious complications, type of infectious agent and therapy, as well as by providing corresponding biosamples, the cohort will establish the foundation for a broad spectrum of studies in the field of infectious diseases and transplant medicine. By January 2020, baseline data and biosamples of about 1400 patients have been collected. We plan to recruit 3500 patients by 2023, and continue follow-up visits and the documentation of infectious events at least until 2025. Information about the DZIF Transplant Cohort is available at https://www.dzif.de/en/working-group/transplant-cohort. [ABSTRACT FROM AUTHOR]

Published
2021
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26. Phages against Noncapsulated Klebsiella pneumoniae: Broader Host range, Slower Resistance

Author

Lourenço, Marta, Osbelt, Lisa, Passet, Virginie, Gravey, François, Megrian, Daniela, Strowig, Till, Rodrigues, Carla, Brisse, Sylvain, Biodiversité et Epidémiologie des Bactéries pathogènes - Biodiversity and Epidemiology of Bacterial Pathogens, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Helmholtz Centre for Infection Research (HZI), German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), Dynamique Microbienne associée aux Infections Urinaires et Respiratoires (DYNAMICURE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Microbiologie structurale - Structural Microbiology (Microb. Struc. (UMR_3528 / U-Pasteur_5)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), This work was mainly supported by the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR) project CRISPR-ATTACK (Advancing CRISPR antimicrobials to combat the bacterial pathogen Klebsiella pneumoniae) under the French Agence Nationale de la Recherche grant ANR-18-JAM2-0004-04, S.B. and 01KI1824 to T.S. C.R. was also supported financially by a Pasteur-Roux fellowship by the Institut Pasteur. The BEBP laboratory is supported by the French Government Investissement d’Avenir Program Laboratoire d’Excellence, Integrative Biology of Emerging Infectious Diseases (ANR10LABX62IBEID). T.S. was also supported by the Federal Ministry of Science under the project DF-AMR2:DECOLONIZE (01KI2131), JPI-AMR Germany (01KI1824) as well as by the German Center for Infection Research (DZIF, TTU 06.826)., We thank Olaya Rendueles Garcia and Eduardo Rocha for sharing the mutant strains that were used for the anti-Kd phage isolation. We thank the Biomics Platform, C2RT, Institut Pasteur, Paris, France, supported by France Génomique (ANR-10-INBS-09-09) and IBISA, especially Marc Monot, Elodie Turc, Laure Lemée and Georges Haustant, for the sequencing project management, the preparation of the genomic libraries, and the sequencing. We thank Melanie Hennart for the bioinformatics methodological input and Anne-Marie Wehenkel for the help with the protein analyses. We are grateful to Jin-Town Wang for sharing the strain NTUH-K2044. We thank Quentin Lamy-Besnier, Chiara Crestani, and Olaya Rendueles Garcia for the critical reading of the manuscript., ANR-18-JAM2-0004,CRISPRattacK(2018), and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)

Subjects
Klebsiella pneumoniae, in vivo, bacteriophages, phage therapy, bacteriophage-bacteria interactions, phage resistance, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, genomics, host range, bacteriophage therapy, antimicrobial resistance, noncapsulated mutants, phage-bacteria interactions
Abstract

International audience; Klebsiella pneumoniae (Kp), a human gut colonizer and opportunistic pathogen, is a major contributor to the global burden of antimicrobial resistance. Virulent bacteriophages represent promising agents for decolonization and therapy. However, the majority of anti-Kp phages that have been isolated thus far are highly specific to unique capsular types (anti-K phages), which is a major limitation to phage therapy prospects due to the highly polymorphic capsule of Kp. Here, we report on an original anti-Kp phage isolation strategy, using capsule-deficient Kp mutants as hosts (anti-Kd phages). We show that anti-Kd phages have a broad host range, as the majority are able to infect noncapsulated mutants of multiple genetic sublineages and O-types. Additionally, anti-Kd phages induce a lower rate of resistance emergence in vitro and provide increased killing efficiency when in combination with anti-K phages. In vivo, anti-Kd phages are able to replicate in mouse guts colonized with a capsulated Kp strain, suggesting the presence of noncapsulated Kp subpopulations. The original strategy proposed here represents a promising avenue that circumvents the Kp capsule host restriction barrier, offering promise for therapeutic development.IMPORTANCE Klebsiella pneumoniae (Kp) is an ecologically generalist bacterium as well as an opportunistic pathogen that is responsible for hospital-acquired infections and a major contributor to the global burden of antimicrobial resistance. In the last decades, limited advances have been made in the use of virulent phages as alternatives or complements to antibiotics that are used to treat Kp infections. This work demonstrates the potential value of an anti-Klebsiella phage isolation strategy that addresses the issue of the narrow host range of anti-K phages. Anti-Kd phages may be active in infection sites in which capsule expression is intermittent or repressed or in combination with anti-K phages, which often induce the loss of capsule in escape mutants.

Published
2023

27. MDR M. tuberculosis outbreak clone in Eswatini missed by Xpert has elevated bedaquiline resistance dated to the pre-treatment era

Author

Elisabeth Sanchez-Padilla, Nazir Ahmed Ismail, Thomas Kohl, Christian Utpatel, Patrick Beckert, Stefan Niemann, Claudio U. Köser, Harald Hoffmann, Sönke Andres, Robin M. Warren, Bouke C. de Jong, Marisa Klopper, Matthias Merker, Florian P. Maurer, Shaheed V. Omar, Katharina Kranzer, Maryline Bonnet, Bernhard Kerschberger, Viola Dreyer, Ivan Barilar, Elisa Ardizzoni, Birgit Schramm, Gugu Maphalala, Forschungszentrum Borstel - Research Center Borstel, German Center for Infection Research (DZIF), Heidelberg University, Epicentre [Paris] [Médecins Sans Frontières], University of Cambridge [UK] (CAM), National Institute for Communicable Diseases [Johannesburg] (NICD), University of Pretoria [South Africa], University of the Witwatersrand [Johannesburg] (WITS), Stellenbosch University, Institute of Tropical Medicine [Antwerp] (ITM), London School of Hygiene and Tropical Medicine (LSHTM), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), Université Montpellier 1 (UM1)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM), Infectious and Tropical Diseases Department [Montpellier], Institut de Recherche pour le Développement (IRD)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Namibia (UNAM), Parts of this work have been supported by the European Union TB-PAN-NET (FP7-223681) project, by Médecins Sans Frontières-Switzerland, and by German Center for Infection Research, Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germanys Excellence Strategy – EXC 2167, and Leibniz Science Campus Evolutionary Medicine of the LUNG (EvoLUNG). The funders had no role in the study design, in the collection, analysis, and interpretation of the data, in the writing of the report, and in the decision to submit the paper for publication., European Project: 223681,EC:FP7:HEALTH,FP7-HEALTH-2007-B,TB PAN-NET(2009), Niemann, Stefan [0000-0002-6604-0684], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, MESH: Mycobacterium tuberculosis, Antitubercular Agents, Drug resistance, Multidrug resistance, Disease Outbreaks, Clofazimine, chemistry.chemical_compound, Tuberculosis, Multidrug-Resistant, MESH: Disease Outbreaks, Diarylquinolines, MESH: Bacterial Proteins, Genetics (clinical), MESH: Microbial Sensitivity Tests, Resistance mutation, MESH: Diarylquinolines, Mycobacterium tuberculosis complex, Molecular Medicine, medicine.drug, MESH: Mutation, Tuberculosis, 030106 microbiology, Microbial Sensitivity Tests, Biology, 03 medical and health sciences, Bacterial Proteins, MESH: Eswatini, Genetics, medicine, Humans, Molecular Biology, MESH: Tuberculosis, Multidrug-Resistant, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Diagnostice escape, Research, MESH: Clone Cells, Resistance evolution, Treatment escape, Mycobacterium tuberculosis, rpoB, medicine.disease, biology.organism_classification, MESH: Antitubercular Agents, Virology, Clone Cells, Multiple drug resistance, MDR outbreak strains, 030104 developmental biology, chemistry, Treatment failure, Mutation, Bedaquiline, Eswatini
Abstract

Background Multidrug-resistant (MDR) Mycobacterium tuberculosis complex strains not detected by commercial molecular drug susceptibility testing (mDST) assays due to the RpoB I491F resistance mutation are threatening the control of MDR tuberculosis (MDR-TB) in Eswatini. Methods We investigate the evolution and spread of MDR strains in Eswatini with a focus on bedaquiline (BDQ) and clofazimine (CFZ) resistance using whole-genome sequencing in two collections ((1) national drug resistance survey, 2009–2010; (2) MDR strains from the Nhlangano region, 2014–2017). Results MDR strains in collection 1 had a high cluster rate (95%, 117/123 MDR strains) with 55% grouped into the two largest clusters (gCL3, n = 28; gCL10, n = 40). All gCL10 isolates, which likely emerged around 1993 (95% highest posterior density 1987–1998), carried the mutation RpoB I491F that is missed by commercial mDST assays. In addition, 21 (53%) gCL10 isolates shared a Rv0678 M146T mutation that correlated with elevated minimum inhibitory concentrations (MICs) to BDQ and CFZ compared to wild type isolates. gCL10 isolates with the Rv0678 M146T mutation were also detected in collection 2. Conclusion The high clustering rate suggests that transmission has been driving the MDR-TB epidemic in Eswatini for three decades. The presence of MDR strains in Eswatini that are not detected by commercial mDST assays and have elevated MICs to BDQ and CFZ potentially jeopardizes the successful implementation of new MDR-TB treatment guidelines. Measures to limit the spread of these outbreak isolates need to be implemented urgently.

Published
2020

28. The Spatial Heterogeneity of the Gut Limits Predation and Fosters Coexistence of Bacteria and Bacteriophages

Author

Luisa De Sordi, Thierry Pedron, Claudia Eberl, Lorenzo Chaffringeon, Quentin Lamy-Besnier, Pascal Campagne, Marion Bérard, Laurent Debarbieux, Bärbel Stecher, Marta Lourenço, Bactériophage, bactérie, hôte - Bacteriophage, bacterium, host, Institut Pasteur [Paris], Collège doctoral [Sorbonne universités], Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Max von Pettenkofer-Institut for Hygiene and Medical Microbiology, Ludwig-Maximilians-Universität München (LMU), Animalerie centrale (Plate-forme), German Center for Infection Research, Partnersite Munich (DZIF), Institut Carnot Pasteur Maladie Infectieuse ANR-11-CARN-017-01, M.L. is part of the Pasteur - Paris University (PPU) International PhD Program. M.L. is funded by Institut Carnot Pasteur Maladie Infectieuse (ANR 11-CARN 017-01). L.D.S. is funded by a Roux-Cantarini fellowship from the Institut Pasteur (Paris, France). L.C. is funded by a PhD fellowships from the Ministère de l’Enseignement Supérieur et de la Recherche, France, École Doctorale n°394. Q.L.-B. is funded by École Doctorale FIRE - Program Bettencourt. B.S. is supported by the German Center of Infection Research (DZIF), the Center for Gastrointestinal Microbiome Research (CEGIMIR), the DFG, Germany, Priority Programme SPP1656 (STE 1971/4-2 and STE 1971/6-1), and the Collaborative Research Center CRC 1371., We thank Harald Brüssow for critically reading the manuscript and Jorge Moura de Sousa for valuable discussion and opinion on early versions of the manuscript. We thank Dwayne Roach and Anne Chevallereau for valuable discussions. We thank Sean Benler for kindly sharing the comprehensive HMM database of Ig-like domains identified on Pfam database. We thank the members of the Centre for Gnotobiology Platform of the Institut Pasteur (Thierry Angélique, Eddie Maranghi, Martine Jacob, and Marisa Gabriela Lopez Dieguez) for their help with the animal work. We thank Cédric Fund for 16S libraries and sequencing from the Biomics Platform, C2RT, Institut Pasteur, Paris, France, supported by France Génomique (ANR-10-INBS-09-09) and IBISA., Institut Pasteur [Paris] (IP), Collège Doctoral, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Cova Rodrigues, Ana

Subjects
Male, Phage therapy, enteroaggregative, medicine.medical_treatment, viruses, [SDV]Life Sciences [q-bio], murine intestine, Gut flora, medicine.disease_cause, gnotobiotic mice, Microbiology, Predation, 03 medical and health sciences, Feces, Mice, 0302 clinical medicine, Virology, medicine, Escherichia coli, microbiota, Animals, Germ-Free Life, Bacteriophages, mucosa, Ecosystem, intestinal microbes, 030304 developmental biology, 0303 health sciences, Mucous Membrane, Oligo mouse microbiota, biology, Bacteria, Ecological dynamics, gut biogeography, biology.organism_classification, Spatial heterogeneity, Gastrointestinal Microbiome, [SDV] Life Sciences [q-bio], Gastrointestinal Tract, Mice, Inbred C57BL, Models, Animal, Microbial Interactions, Parasitology, Female, 030217 neurology & neurosurgery
Abstract

International audience; The ecological dynamics underlying the coexistence between antagonistic populations of bacteria and their viruses, bacteriophages (phages), in the mammalian gut microbiota remain poorly understood. We challenged a murine synthetic bacterial community with phages to study the factors allowing phages-bacteria coexistence. Coexistence was not dependent on the development of phage-resistant clones nor on the ability of phages to extend their host range. Instead, our data suggest that phage-inaccessible sites in the mucosa serve as a spatial refuge for bacteria. From there, bacteria disseminate in the gut lumen where they are predated by luminal phages fostering the presence of intestinal phage populations. The heterogeneous biogeography of microbes contributes to the long-term coexistence of phages with phage-susceptible bacteria. This observation could explain the persistence of intestinal phages in humans as well as the low efficiency of oral phage therapy against enteric pathogens in animal models and clinical trials.

Published
2020

29. De novo protein design enables the precise induction of RSV-neutralizing antibodies

Author

Sean Ervin, Jean-François Eléouët, Sabrina Vollers, Marie-Anne Rameix-Welti, Marie Galloux, Stéphane Rosset, Jean-Philippe Julien, Xiaolin Wen, Yuxing Li, Johannes T. Cramer, Che Yang, Jaume Bonet, Thomas Krey, Theodore S. Jardetzky, Patricia Corthésy, Yimeng Wang, Sabine Riffault, Chi-I Chiang, Iga Kucharska, Delphyne Descamps, Elie Dheilly, Sandrine Georgeon, Giacomo Castoro, Mélanie Villard, Charles-Adrien Richard, Teresa C. Delgado, Fabian Sesterhenn, Elisa Oricchio, Vicente Mas, Luciano A. Abriata, Bruno E. Correia, John T. Bates, Instituto de Salud Carlos III, European Research Council, Swiss National Science Foundation, Stavros Niarchos Foundation, EPFL Postdoctoral Fellows, German Center for Infection Research (Alemania), Deutsche Forschungsgemeinschaft (Alemania), Federal Ministry of Education & Research (Alemania), Canada Research Chairs, NIH - National Institute of Allergy and Infectious Diseases (NIAID) (Estados Unidos), Ecole Polytechnique Fédérale de Lausanne (EPFL), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL), Hannover Medical School [Hannover] (MHH), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, University of Maryland [Baltimore], The Hospital for sick children [Toronto] (SickKids), Department of Biochemistry [University of Toronto], University of Toronto, Virologie et Immunologie Moléculaires (VIM (UR 0892)), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Swiss Institute for Experimental Cancer Research - Lausanne (ISREC), Swiss Institute for Experimental Cancer Research, Centro Nacional de Microbiología [ISCIII, Madrid, Spain] (CNM), Instituto de Salud Carlos III [Madrid] (ISC), Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Wake Forest Baptist Medical Center, University of Mississippi Medical Center (UMMC), University of Maryland School of Medicine, University of Maryland System, German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), University of Luebeck, INSTITUT FUR ANGEWANDTE BODENBIOLOGIE GMBH HAMBURG DEU, Partenaires IRSTEA, Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), European Project: 716058,DeNovoImmunoDesign, Université de Lausanne = University of Lausanne (UNIL), and European Project: 716058,EXCELLENT SCIENCE - European Research Council (ERC),ERC-2016-STG - ERC Starting Grant,DeNovoImmunoDesign(2017)

Subjects
Immunogen, medicine.drug_class, Protein Conformation, Recombinant Fusion Proteins, Protein design, Amino Acid Motifs, computational design, Computational biology, Biology, Monoclonal antibody, Protein Engineering, Epitope, Article, Affinity maturation, 03 medical and health sciences, 0302 clinical medicine, Antigen, backbone, medicine, Respiratory Syncytial Virus Vaccines, Humans, b-cells, 030304 developmental biology, affinity maturation, 0303 health sciences, epitope, Multidisciplinary, dengue virus, Immunodominant Epitopes, Computational Biology, fusion-glycoprotein vaccine, Single-Domain Antibodies, [SHS.ECO]Humanities and Social Sciences/Economics and Finance, Fusion protein, Antibodies, Neutralizing, 3. Good health, nmr structure determination, Respiratory Syncytial Virus, Human, biology.protein, potent, Antibody, influenza, 030217 neurology & neurosurgery
Abstract

De novo protein design has been successful in expanding the natural protein repertoire. However, most de novo proteins lack biological function, presenting a major methodological challenge. In vaccinology, the induction of precise antibody responses remains a cornerstone for next-generation vaccines. Here, we present a protein design algorithm called TopoBuilder, with which we engineered epitope-focused immunogens displaying complex structural motifs. In both mice and nonhuman primates, cocktails of three de novo-designed immunogens induced robust neutralizing responses against the respiratory syncytial virus. Furthermore, the immunogens refocused preexisting antibody responses toward defined neutralization epitopes. Overall, our design approach opens the possibility of targeting specific epitopes for the development of vaccines and therapeutic antibodies and, more generally, will be applicable to the design of de novo proteins displaying complex functional motifs. This work was supported by the swiss initiative for systems biology (SystemsX.ch), the European Research Council (Starting grant - 716058), the Swiss National Science Foundation (310030_163139) and the EPFL’s Catalyze4Life initiative. F.S. was supported by an SNF/Innosuisse BRIDGE Proof-of-Concept grant. J.B. was supported by the EPFL Fellows postdoctoral fellowship. T.K. received funding from the German Center of Infection Research (DZIF) and the Cluster of Excellence RESIST (EXC 2155) of the German Research foundation. J.T.C. was funded by the ERA-Net PrionImmunity project 01GM1503 (Federal Ministry of Education and Research, Germany). V.M. received funding from “AESI-18” (Instituto de Salud Carlos III), grant MPY 375/18. J.PJ. was funded by the Canada Research Chairs program (J.P.J.), T.J. and X.W. were funded by the NIH NIAID (R01 AI137523). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Sí

Published
2020

30. Relevance of Assembly-Activating Protein for Adeno-associated Virus Vector Production and Capsid Protein Stability in Mammalian and Insect Cells

Author

Manuel Gunkel, Kathleen Börner, Stefanie Grosse, Lucie Ménard, Ellen Wiedtke, Eduard Ayuso, Chiara Krämer, Julia Fakhiri, Anne-Kathrin Herrmann, Magalie Penaud-Budloo, Dirk Grimm, Vibor Laketa, Department of Infectious Diseases/Virology [Heidelberg, Germany] (Cluster of Excellence CellNetworks), Universität Heidelberg [Heidelberg], BioQuant Center [Heidelberg, Germany], Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques (Inserm UMR 1089), 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), German Center for Infection Research [Heidelberg, Germany] (DZIF), Heidelberg University, CellNetworks Advanced Biological Screening Facility [Heidelberg, Germany], A.-K.H. and D.G. gratefully acknowledge support from Collaborative Research Center SFB1129 (project TP2, Deutsche Forschungsgemeinschaft [DFG]). D.G. and his lab are further thankful for support from Collaborative Research Center TRR179 (project TP18, DFG). S.G., A.-K.H., E.W., and D.G. are grateful for funding from the Cluster of Excellence CellNetworks at Heidelberg University (funded by the DFG [EXC81]). J.F. appreciates a PhD stipend from the Hartmut Hoffmann-Berling International Graduate School (HBIGS) at Heidelberg University. M.P.-B. and E.A. acknowledge support from Institut National de la Santé et la Recherche Médicale (INSERM), CHU Nantes, University of Nantes, and the Association Française contre les Myopathies (AFM). K.B., V.L. and D.G. gratefully acknowledge funding through the German Center for Infection Research (DZIF, TTU HIV). S.G., C.K., and D.G. further acknowledge support through a research collaboration with the company Baxalta Inc./Shire., JAULIN, Nicolas, Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Proteasome Endopeptidase Complex, Insecta, viruses, [SDV]Life Sciences [q-bio], Genetic Vectors, Immunology, adeno-associated virus, Biology, medicine.disease_cause, Microbiology, Virus, law.invention, Gene Delivery, 03 medical and health sciences, Plasmid, law, Virology, Sf9 Cells, medicine, Animals, Humans, Vector (molecular biology), capsid assembly, Adeno-associated virus, Mammals, AAP, Protein Stability, Virus Assembly, parvovirus, Virion, AAV, Dependovirus, assembly-activating protein, [SDV] Life Sciences [q-bio], Open reading frame, 030104 developmental biology, Capsid, Insect Science, Recombinant DNA, Capsid Proteins, Proteasome Inhibitors, Nuclear localization sequence, HeLa Cells
Abstract

The discovery that adeno-associated virus 2 (AAV2) encodes an eighth protein, called assembly-activating protein (AAP), transformed our understanding of wild-type AAV biology. Concurrently, it raised questions about the role of AAP during production of recombinant vectors based on natural or molecularly engineered AAV capsids. Here, we show that AAP is indeed essential for generation of functional recombinant AAV2 vectors in both mammalian and insect cell-based vector production systems. Surprisingly, we observed that AAV2 capsid proteins VP1 to -3 are unstable in the absence of AAP2, likely due to rapid proteasomal degradation. Inhibition of the proteasome led to an increase of intracellular VP1 to -3 but neither triggered assembly of functional capsids nor promoted nuclear localization of the capsid proteins. Together, this underscores the crucial and unique role of AAP in the AAV life cycle, where it rapidly chaperones capsid assembly, thus preventing degradation of free capsid proteins. An expanded analysis comprising nine alternative AAV serotypes (1, 3 to 9, and rh10) showed that vector production always depends on the presence of AAP, with the exceptions of AAV4 and AAV5, which exhibited AAP-independent, albeit low-level, particle assembly. Interestingly, AAPs from all 10 serotypes could cross-complement AAP-depleted helper plasmids during vector production, despite there being distinct intracellular AAP localization patterns. These were most pronounced for AAP4 and AAP5, congruent with their inability to rescue an AAV2/AAP2 knockout. We conclude that AAP is key for assembly of genuine capsids from at least 10 different AAV serotypes, which has implications for vectors derived from wild-type or synthetic AAV capsids. IMPORTANCE Assembly of adeno-associated virus 2 (AAV2) is regulated by the assembly-activating protein (AAP), whose open reading frame overlaps with that of the viral capsid proteins. As the majority of evidence was obtained using virus-like particles composed solely of the major capsid protein VP3, AAP's role in and relevance for assembly of genuine AAV capsids have remained largely unclear. Thus, we established a trans -complementation assay permitting assessment of AAP functionality during production of recombinant vectors based on complete AAV capsids and derived from any serotype. We find that AAP is indeed a critical factor not only for AAV2, but also for generation of vectors derived from nine other AAV serotypes. Moreover, we identify a new role of AAP in maintaining capsid protein stability in mammalian and insect cells. Thereby, our study expands our current understanding of AAV/AAP biology, and it concomitantly provides insights into the importance of AAP for AAV vector production.

Published
2017

31. Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence

Author

Verena Königer, D. Scott Merrell, Roman Andriiovych Moskalenko, Rainer Haas, Thomas Borén, Sara Henriksson, Jafar Mahdavi, Abhijit Chowdhury, Johan Ögren, Anders Hofer, Jay V. Solnick, Dan Danielsson, Sara K. Lindén, Dag Ilver, Konstantinos S. Papadakos, Susanne Vikström, Jörgen Ådén, Jan Holgersson, Gerhard Gröbner, Alexej Schmidt, Jeanna Bugaytsova, Oscar Björnham, Göran O. Bylund, Rolf Sjöström, Stefan Oscarson, Dionyssios N. Sgouras, Lori M. Hansen, Yevgen A Chernov, Anders Esberg, Kristof Moonens, Christopher Aisenbrey, Charles Kelly, Ludmilla A. Morozova-Roche, Jeannette M. Whitmire, Beatriz Martinez-Gonzalez, Asish K. Mukhopadhyay, Angela Eldridge, Nicklas Strömberg, Robert H. Gilman, Andre Dubois, Lars Engstrand, Staffan Schedin, Brett A. Chromy, Justine Younson, Matthew Goldman, Anna Shevtsova, Macarena P. Quintana-Hayashi, Hui Liu, Magnus Unemo, Lena Rakhimova, Anna Åberg, Sebastian Suerbaum, Anna Arnqvist, Pär Gideonsson, Maréne Landström, Douglas E. Berg, Kristoffer Brännström, Anders Olofsson, Melissa Mendez, G. Balakrish Nair, Han Remaut, Umeå University, School of Life Sciences, University of Nottingham, UK (UON), Sahlgrenska Academy at University of Gothenburg [Göteborg], Université libre de Bruxelles (ULB), VIB-VUB Center for Structural Biology [Bruxelles], VIB [Belgium], Sumy State University, Max Von Pettenkofer Institute (MVP), Ludwig-Maximilians-Universität München (LMU), Uniformed Services University of the Health Sciences (USUHS), King‘s College London, Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU), School of Digestive and Liver Diseases [Kolkata] (SDLD), National Institute of Cholera and Enteric Diseases, Translational Health Science and Technology Institute [Faridabad] (THSTI), Institut Pasteur Hellénique, Réseau International des Instituts Pasteur (RIIP), Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Karolinska Institutet [Stockholm], Örebro University Hospital [Örebro, Sweden], Hannover Medical School [Hannover] (MHH), German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), School of Chemistry and Chemical Biology (UCD), University College Dublin [Dublin] (UCD), University of California [Davis] (UC Davis), University of California, German Center for Infection Research, Partnersite Munich (DZIF), Département d'Informatique [Bruxelles] (ULB), Faculté des Sciences [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), University of California [San Diego] (UC San Diego), This work was supported by grants from Vetenskapsrådet (VR/M) to T.B. and S.K.L., Cancerfonden to T.B. and A.A., VR/NT to A.A. and S. Schedin, Formas to S.K.L., the J.C. Kempe and Seth M. Kempe Memorial Foundation, the Knut and Alice Wallenberg Foundation (2012.0090) to T.B. and M.L., European Union Seventh Framework Program GastricGlycoExplorer ITN grant number 316929 to T.B. and Y.A.C., Magn. Bergvall’s Foundation to S. Schedin, DFG (SFB 900/A1) to S. Suerbaum, DFG (HA2697/16-1) to R.H., FP6 ANR-06-PATHO-00701 ERA-NET and Actions Concertées Inter-Pasteuriennes (ACIP) (2006) to D.N.S., NIH R01DK063041 to D.E.B., NIH CA082312 to D.S.M., NIH AI070803 and AI081037 to J.V.S., CSIR project, India (No. 37(1640)/14/EMR –II) to A.K.M., and VIB and FWO (grants: G033717N and 12H8416N) to K.M. and H.R., This paper is dedicated to the memory of our friend, collaborator, and co-author Dr. Andre Dubois, a great scientist who contributed importantly both intellectually and materially to this project. We thank S. Michopoulos and G. Mantzaris for H. pylori clinical isolates and Ö. Furberg (NoPolo.se), N. Ulander (softplanbangkok.com), S. Lindström, and M. Borén for the digital movie, tech, art, and figure work, respectively., Vrije Universiteit Brussel, Basic (bio-) Medical Sciences, Structural Biology Brussels, and Department of Bio-engineering Sciences

Subjects
0301 basic medicine, MESH: Hydrogen-Ion Concentration, Gastric acidity, MESH: Helicobacter Infections/pathology, MESH: Helicobacter pylori/physiology, Disease, adaptation, Bacterial Adhesion, polymorphism, acid responsiveness, MESH: Bacterial Adhesion, Bacterial, Hydrogen-Ion Concentration, gastric acidity, Adhesins, 3. Good health, Cell and molecular biology, medicine.anatomical_structure, Infectious Diseases, MESH: Gastric Mucosa/microbiology, Medical Microbiology, 030106 microbiology, Immunology, Digestive Diseases - (Peptic Ulcer), Biology, blood group antigen-binding adhesion, Microbiology, Helicobacter Infections, diversity, Vaccine Related, 03 medical and health sciences, Virology, ABO blood group system, Biodefense, Gastric mucosa, medicine, MESH: Helicobacter Infections/microbiology, multimerization, Adhesins, Bacterial, subpopulations, Helicobacter pylori, Prevention, gastric cancer, MESH: Adhesins, Bacterial/metabolism, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: Gastric Mucosa/pathology, Bacterial adhesin, Chronic infection, 030104 developmental biology, Emerging Infectious Diseases, Gastric Mucosa, Parasitology, Digestive Diseases
Abstract

The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen andthat bio-selection and changes in BabA bindingproperties through mutation and recombination with babA-related genes are selected by differencesamong individuals and by changes in gastric acidity over time. These processes generate diverse H.pylori subpopulations, in which BabA's adaptive evolution contributes to H.pylori persistence and overt gastric disease.

Published
2017

32. Virological efficacy of 24-week fozivudine-based regimen in ART-naive patients from Tanzania and Cote d'Ivoire

Author

Tessa Lennemann, Pierre-Marie Girard, Alain Pruvost, Raoul Moh, Xavier Anglaret, Lucas Maganga, Friedrich von Massow, Jimson Mgaya, Serge Eholié, Frederic N. Ello, Christine Danel, Michael Hoelscher, Ralph Zuhse, Arne Kroidl, Elmar Saathoff, Division of Infectious Diseases and Tropical Medicine, Ludwig Maximilians University of Munich, German Center for Infection Research (DZIF), Programme PAC Cote Ivoire, Centre Hospitalier Universitaire de Treichville (CHU de Treichville), Service des Maladies Infectieuses et Tropicales, NIMR, Mbeya Medical Research Center, Mbeya Medical Research Center (MMRC), Laboratoire d'Etudes et de Recherches en Immunoanalyses (LERI), Service de Pharmacologie et Immunoanalyse (SPI), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Médicaments et Technologies pour la Santé (MTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Paris-Saclay, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Infectious Diseases, University of Gothenburg (GU), Chiracon - Biotechnology Park/TGZ I, Helmholtz-Zentrum München (HZM), Institute for Life Sciences and Environment (i-LSE), German Ministry for Science and Education (BMBF) [01KA1201], German Center for Infection Research (DZIF) [TTU 04.703], French Agence Nationale de Recherches sur le Sida (ANRS), European Project: 304786, Ludwig-Maximilians University [Munich] (LMU), and Helmholtz Zentrum München = German Research Center for Environmental Health

Subjects
Male, 0301 basic medicine, Sustained Virologic Response, [SDV]Life Sciences [q-bio], HIV Infections, Tanzania, law.invention, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Antiretroviral Therapy, Highly Active, Immunology and Allergy, Medicine, Prospective Studies, 030212 general & internal medicine, Lamivudine, Middle Aged, Clinical Science, Lipids, 3. Good health, zidovudine, Treatment Outcome, Infectious Diseases, Anti-Retroviral Agents, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Female, medicine.drug, Adult, medicine.medical_specialty, Efavirenz, Drug-Related Side Effects and Adverse Reactions, Immunology, antiretroviral therapy, Neutropenia, 03 medical and health sciences, Zidovudine, Internal medicine, Humans, fozivudine, Dosing, business.industry, HIV, medicine.disease, 030112 virology, Clinical trial, Regimen, Cote d'Ivoire, chemistry, Africa, business
Abstract

Supplemental Digital Content is available in the text, Objective: Use of zidovudine (ZDV) in antiretroviral therapy is limited by toxicity and twice daily (b.i.d.) dosing. Fozivudine (FZD) is a ZDV prodrug, which is activated intracellularly to ZDV-monophosphate especially in mononuclear cells but not in bone marrow cells. FZD promises improved myelotoxicity and once daily (o.d.) dosing. Design: Randomized clinical trial. Methods: We conducted an open-label, phase II, proof-of-concept trial investigating three different FZD doses (800 mg o.d., 600 mg b.i.d., 1200 mg o.d.) versus ZDV (300 mg b.i.d.) in combination with lamivudine and efavirenz in HIV-infected, ART-naive patients from Tanzania and Côte d’Ivoire. The primary objective was to demonstrate virological efficacy after 24 weeks in intent-to treat and per-protocol analysis. Secondary endpoints included safety and pharmacokinetic outcomes. Results: Of 119 participants included in the intent-to treat analysis, HIV RNA less than 50 copies/ml at 24 weeks was observed in 64 of 88 (73%) patients in the combined FZD arms versus 24 of 31 (77%) in the ZDV arm (RR 0.94, 95% confidence interval 0.75–1.18). In the per-protocol analysis, responses were 64 of 77 (87%) versus 23 of 29 (79%), respectively (RR 1.09, 95% confidence interval 0.89–1.34). Outcomes were similar between FZD arms. Overall, treatments were well tolerated. Severe or worse anaemia occurred in two cases (one related to FZD, one to ZDV), grade III/IV neutropenia was less frequent in FZD compared with ZDV arms (22 versus 42%, P = 0.035). Pharmacokinetic analysis supported o.d. administration of FZD. Conclusion: Virological 24-week efficacy was demonstrated in b.i.d. and o.d. administered FZD-based regimens. Reduced myelotoxicity of FZD needs to be confirmed in a larger trial.

Published
2017

33. Contribution of alcohol use in HIV/hepatitis C virus co-infection to all-cause and cause-specific mortality: A collaboration of cohort studies

Author

Trickey, Adam, Ingle, Suzanne M, Boyd, Anders, Gill, M John, Grabar, Sophie, Jarrin-Vera, Inmaculada, Obel, Niels, Touloumi, Giota, Zangerle, Robert, Rauch, Andri, Rentsch, Christopher T, Satre, Derek D, Silverberg, Michael J, Bonnet, Fabrice, Guest, Jodie, Burkholder, Greer, Crane, Heidi, Teira, Ramon, Berenguer, Juan, Wyen, Christoph, Abgrall, Sophie, Hessamfar, Mojgan, Reiss, Peter, d'Arminio Monforte, Antonella, McGinnis, Kathleen A, Sterne, Jonathan A C, Wittkop, Linda, Antiretroviral Therapy Cohort Collaboration, NIH - National Institute on Alcohol Abuse and Alcoholism (NIAAA) (Estados Unidos), NIH - National Institute of Allergy and Infectious Diseases (NIAID) (Estados Unidos), United States Department of Veterans Affairs, Instituto de Salud Carlos III, Red de Investigación Cooperativa en Investigación en Sida (España), Plan Nacional de I+D+i (España), Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Swiss National Science Foundation, Ministerio de Sanidad (España), Janssen Cilag, Institut National de la Santé et de la Recherche Médicale (Francia), Wellcome Trust, Gilead Sciences (Spain), Ministère de la Santé (Francia), Austrian Agency for Health and Food Safety, Stichting HIV Monitoring, German Center for Infection Research (Alemania), Ministry of Health Welfare and Sport (Países Bajos), National Institute for Health Research (Reino Unido), Alberta Health (Canadá), Agence Nationale de Recherches sur le sida et les hépatites virales (Francia), ViiV Healthcare, and Integrated Clinical Systems

Subjects
Hepatitis C virus, Cohort, HIV, Mortality, Alcohol, Cause-specific
Abstract

Among persons with HIV (PWH), higher alcohol use and having hepatitis C virus (HCV) are separately associated with increased morbidity and mortality. We investigated whether the association between alcohol use and mortality among PWH is modified by HCV. Data were combined from European and North American cohorts of adult PWH who started antiretroviral therapy (ART). Self-reported alcohol use data, collected in diverse ways between cohorts, were converted to grams/day. Eligible PWH started ART during 2001-2017 and were followed from ART initiation for mortality. Interactions between the associations of baseline alcohol use (0, 0.1-20.0, >20.0 g/day) and HCV status were assessed using multivariable Cox models. Of 58,769 PWH, 29,711 (51%), 23,974 (41%) and 5084 (9%) self-reported alcohol use of 0 g/day, 0.1-20.0 g/day, and > 20.0 g/day, respectively, and 4799 (8%) had HCV at baseline. There were 844 deaths in 37,729 person-years and 2755 deaths in 443,121 person-years among those with and without HCV, respectively. Among PWH without HCV, adjusted hazard ratios (aHRs) for mortality were 1.18 (95% CI: 1.08-1.29) for 0.0 g/day and 1.84 (1.62-2.09) for >20.0 g/day compared with 0.1-20.0 g/day. This J-shaped pattern was absent among those with HCV: aHRs were 1.00 (0.86-1.17) for 0.0 g/day and 1.64 (1.33-2.02) for >20.0 g/day compared with 0.1-20.0 g/day (interaction p

Published
2023

34. Chromosome folding and prophage activation reveal specific genomic architecture for intestinal bacteria

Author

Lamy-Besnier, Quentin, Bignaud, Amaury, Garneau, Julian, Titecat, Marie, Conti, Devon, von Strempel, Alexandra, Monot, Marc, Stecher, Bärbel, Koszul, Romain, Debarbieux, Laurent, Marbouty, Martial, Bactériophage, bactérie, hôte - Bacteriophage, bacterium, host, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Régulation spatiale des Génomes - Spatial Regulation of Genomes, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Collège Doctoral, Sorbonne Université (SU), Biomics (plateforme technologique), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Lille, Max Von Pettenkofer Institute (MVP), Ludwig-Maximilians-Universität München (LMU), German Center for Infection Research, Partnersite Munich (DZIF), This research was supported by funding to BS from DFG-STE-1971/11–1 (PhaStGut project), to BS from the European Research Council under the Horizon 2020 Program (ERC grant agreement 865615), to LD and MMa from PRCI ANR-20-CE92-0048 (PhaStGut project), and to RK from the European Research Council under the Horizon 2020 Program (ERC grant agreement 771813) and from JPI-EC-AMR STARCS ANR-16-JPEC-0003–05. QLB received funding from École Doctorale FIRE-Program Bettencourt. AB is supported by an ENS fellowship from the French Ministry of Higher Education, Research and Innovation. MMo and JRG were supported by JCJC ANR-18-CE35-0011 (project CDPhages). MT received funding from DigestScience. Biomics Platform, C2RT, Institut Pasteur, Paris, France, was supported by France Génomique (ANR-10-INBS-09) and IBISA. AB and DC belong to Ecole Doctorale Complexité du vivant ED515 of Sorbonne Université., ANR-20-CE92-0048,PhaStGut,Etude des mécanismes de la coexistence stable entre bactériophages et bactéries et de ses conséquences sur la fonction du microbiote intestinal(2020), ANR-16-JPEC-0003,STARCS,Selection and Transmission of Antimicrobial Resistance in Complex Systems(2016), ANR-18-CE35-0011,CDPhages,Le role des bactériophages dans l'évolution de la virulence chez Clostridium difficile(2018), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), and European Project: 771813,ERC-2017-COG,SynarchiC(2018)

Subjects
Microbiology (medical), MESH: Humans, Virome, MESH: Genomics, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, OMM12, Phages Gut HiC Virome OMM12 3D signatures, Microbiology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: Bacteria, MESH: Prophages, 3D signatures, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Phages, Gut, MESH: Animals, MESH: Ecosystem, MESH: Chromosomes, MESH: Bacteriophages, HiC, MESH: Mice
Abstract

Background Bacteria and their viruses, bacteriophages, are the most abundant entities of the gut microbiota, a complex community of microorganisms associated with human health and disease. In this ecosystem, the interactions between these two key components are still largely unknown. In particular, the impact of the gut environment on bacteria and their associated prophages is yet to be deciphered. Results To gain insight into the activity of lysogenic bacteriophages within the context of their host genomes, we performed proximity ligation-based sequencing (Hi-C) in both in vitro and in vivo conditions on the 12 bacterial strains of the OMM12 synthetic bacterial community stably associated within mice gut (gnotobiotic mouse line OMM12). High-resolution contact maps of the chromosome 3D organization of the bacterial genomes revealed a wide diversity of architectures, differences between environments, and an overall stability over time in the gut of mice. The DNA contacts pointed at 3D signatures of prophages leading to 16 of them being predicted as functional. We also identified circularization signals and observed different 3D patterns between in vitro and in vivo conditions. Concurrent virome analysis showed that 11 of these prophages produced viral particles and that OMM12 mice do not carry other intestinal viruses. Conclusions The precise identification by Hi-C of functional and active prophages within bacterial communities will unlock the study of interactions between bacteriophages and bacteria across conditions (healthy vs disease).

Published
2023

35. Survival trade-offs in plant roots during colonization by closely related beneficial and pathogenic fungi

Author

Soledad Sacristán, Stéphane Hacquard, Michael R. Thon, Kei Hiruma, Ulrike Damm, Paul Schulze-Lefert, Jean-Félix Dallery, Barbara Kracher, Olivier Lespinet, Bernard Henrissat, Philipp C. Münch, Matthieu Hainaut, Richard J. O'Connell, Ruben Garrido-Oter, Alice C. McHardy, Emiel Ver Loren van Themaat, Eric Kemen, Aaron Weimann, Department of Plant Microbe Interactions, Max Planck Institute for Plant Breeding Research (MPIPZ), Max Von Pettenkofer Institute (MVP), Ludwig-Maximilians-Universität München (LMU), German Center for Infection Research - Partner Site Bonn-Cologne (DZIF), Computational Biology of Infection Research [Braunschweig], Helmholtz Centre for Infection Research (HZI), Cluster of Excellence on Plant Sciences (CEPLAS), Department of Algorithmic Bioinformatics, Heinrich-Heine-Universität Düsseldorf [Düsseldorf], Centro Hispano-Luso de Investigaciones Agrarias, Departamento de Microbiología y Genétic, Universidad de Salamanca, Fungal Biodiversity Centre, BIOlogie et GEstion des Risques en agriculture (BIOGER), AgroParisTech-Institut National de la Recherche Agronomique (INRA), Architecture et fonction des macromolécules biologiques (AFMB), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Department of Biological Sciences, King Abdulazziz University, Laboratoire de Recherche en Informatique (LRI), Université Paris-Sud - Paris 11 (UP11)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), BioInformatique Moléculaire (BIM), Département Biologie des Génomes (DBG), Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centro de Biotechnologia y Genomica de Plantas (UPM-INIA) and ETSI Agronomos, Universidad Politécnica de Madrid (UPM), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Max Planck Society, Agence Nationale de la Recherche [ANR-12-CHEX-0008-01], 'Cluster of Excellence on Plant Sciences' program - Deutsche Forschungsgemeinschaft, German Center for Infection Research, DZIF, Japan Society for the Promotion of Science, European Project: 323094,EC:FP7:ERC,ERC-2012-ADG_20120314,ROOTMICROBIOTA(2013), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Hacquard, Stéphane, Kracher, Barbara, and BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106 Braunschweig, Germany.

Subjects
roots, 0301 basic medicine, Colletotrichum tofieldiae, Arabidopsis thaliana, plant innate immunity, Science, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Endophyte, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Symbiosis, Arabidopsis, Colletotrichum incanum, endophyte, genome, transcriptome, differential gene expression, symbiosis, Colonization, Gene, 2. Zero hunger, Genetics, Multidisciplinary, biology, Effector, Host (biology), fungi, food and beverages, General Chemistry, 15. Life on land, biology.organism_classification, 030104 developmental biology, Colletotrichum
Abstract

The sessile nature of plants forced them to evolve mechanisms to prioritize their responses to simultaneous stresses, including colonization by microbes or nutrient starvation. Here, we compare the genomes of a beneficial root endophyte, Colletotrichum tofieldiae and its pathogenic relative C. incanum, and examine the transcriptomes of both fungi and their plant host Arabidopsis during phosphate starvation. Although the two species diverged only 8.8 million years ago and have similar gene arsenals, we identify genomic signatures indicative of an evolutionary transition from pathogenic to beneficial lifestyles, including a narrowed repertoire of secreted effector proteins, expanded families of chitin-binding and secondary metabolism-related proteins, and limited activation of pathogenicity-related genes in planta. We show that beneficial responses are prioritized in C. tofieldiae-colonized roots under phosphate-deficient conditions, whereas defense responses are activated under phosphate-sufficient conditions. These immune responses are retained in phosphate-starved roots colonized by pathogenic C. incanum, illustrating the ability of plants to maximize survival in response to conflicting stresses.

Published
2016

36. Hepatitis D virus interferes with hepatitis B virus RNA production via interferon-dependent and -independent mechanisms

Author

Julie Lucifora, Dulce Alfaiate, Caroline Pons, Maud Michelet, Ricardo Ramirez, Floriane Fusil, Fouzia Amirache, Axel Rossi, Anne-Flore Legrand, Emilie Charles, Serena Vegna, Rayan Farhat, Michel Rivoire, Guillaume Passot, Nicolas Gadot, Barbara Testoni, Charlotte Bach, Thomas F. Baumert, Anastasia Hyrina, Rudolf K. Beran, Fabien Zoulim, Andre Boonstra, Hildegard Büning, Eloi R. Verrier, François-Loïc Cosset, Simon P. Fletcher, Anna Salvetti, David Durantel, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Agents Infectieux [Lyon] (IAI), Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Gilead Sciences, Inc. [Foster City, CA, USA], Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Institute of Experimental Hematology [Hannover, Germany], Hannover Medical School [Hannover] (MHH), Application des ultrasons à la thérapie (LabTAU), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Oncologie Médicale [Centre hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre pour l'innovation en cancérologie de Lyon (CICLY), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre Léon Bérard [Lyon], Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Croix-Rousse [CHU - HCL], Gastroenterology and Hepatology, Erasmus University Medical Center [Rotterdam] (Erasmus MC), German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), and Gastroenterology & Hepatology

Subjects
Hepatology, SDG 3 - Good Health and Well-being, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Sciences du Vivant [q-bio]/Médecine humaine et pathologie
Abstract

Background & Aims: Chronic coinfection with HBV and HDV leads to the most aggressive form of chronic viral hepatitis. Herein, we aimed to elucidate the molecular mechanisms underlying the widely reported observation that HDV interferes with HBV in most coinfected patients. Methods: Patient liver tissues, primary human hepatocytes, HepaRG cells and human liver chimeric mice were used to analyze the effect of HDV on HBV using virological and RNA-sequencing analyses, as well as RNA synthesis, stability and association assays. Results: Transcriptomic analyses in cell culture and mouse models of coinfection enabled us to define an HDV-induced signature, mainly composed of interferon (IFN)-stimulated genes (ISGs). We also provide evidence that ISGs are upregulated in chronically HDV/HBV-coinfected patients but not in cells that only express HDV antigen (HDAg). Inhibition of the hepatocyte IFN response partially rescued the levels of HBV parameters. We observed less HBV RNA synthesis upon HDV infection or HDV protein expression. Additionally, HDV infection or expression of HDAg alone specifically accelerated the decay of HBV RNA, and HDAg was associated with HBV RNAs. On the contrary, HDAg expression did not affect other viruses such as HCV or SARS-CoV-2. Conclusions: Our data indicate that HDV interferes with HBV through both IFN-dependent and IFN-independent mechanisms. Specifically, we uncover a new viral interference mechanism in which proteins of a satellite virus affect the RNA production of its helper virus. Exploiting these findings could pave the way to the development of new therapeutic strategies against HBV. Impact and implications: Although the molecular mechanisms remained unexplored, it has long been known that despite its dependency, HDV decreases HBV viremia in patients. Herein, using in vitro and in vivo models, we showed that HDV interferes with HBV through both IFN-dependent and IFN-independent mechanisms affecting HBV RNA metabolism, and we defined the HDV-induced modulation signature. The mechanisms we uncovered could pave the way for the development of new therapeutic strategies against HBV by mimicking and/or increasing the effect of HDAg on HBV RNA. Additionally, the HDV-induced modulation signature could potentially be correlated with responsiveness to IFN-α treatment, thereby helping to guide management of HBV/HDV-coinfected patients.

Published
2023

37. HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice

Author

Michel C. Nussenzweig, Elena Knops, Michael S. Seaman, Pamela J. Bjorkman, Eva Billerbeck, Joshua A. Horwitz, Hildegard Büning, Ariel Halper-Stromberg, Marine Malbec, Olivier Schwartz, Rolf Kaiser, Alexander Ploss, Charles M. Rice, Thomas Eisenreich, Alexander D. Gitlin, Hugo Mouquet, Florian Klein, Marcus Dorner, Anna Tretiakova, Sophia Gravemann, James M. Wilson, Laboratory of Molecular Immunology, Rockefeller University [New York], Réponse humorale aux pathogènes, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Department of Pathology and Laboratory Medicine, University of Pennsylvania, Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institute for Virology, University of Cologne, Laboratory of Virology and Infectious Disease, Rockefeller University [New York]-Center for the Study of Hepatitis C, Beth Israel Deaconess Medical Center, Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS)-Harvard Medical School [Boston] (HMS), Department of Molecular Biology, Princeton University, Division of Biology and Howard Hughes Medical Institute, California Institute of Technology (CALTECH), Howard Hughes Medical Institute (HHMI), supported by grants from the Agence Nationale de Recherche sur le Sida, Sidaction, AREVA Foundation, Vaccine Research Institute, the Labex Integrative Biology of Emerging Infectious Diseases program, the Seventh Framework ProgrammeHIT Hidden HIV (Health-F3-2012-305762), and Institut Pasteur. This work was supported in part by the Bill and Melinda Gates Foundation with Comprehensive Antibody Vaccine Immune Monitoring Consortium Grant 1032144 (to M.S.S.) and Collaboration for AIDS Vaccine Discovery Grants 38660 (to P.J.B.) and 38619s (to M.C.N.). This work was also supported by the German Center for Infection Research (S.G. and H.B.), UL1 TR000043 Translational Science Award (Clinical and Translational Science Award) program, AI 100663-01 (to M.C.N.), Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, and AI 100148-01 (to P.J.B. and M.C.N.). P.J.B. and M.C.N. are Howard Hughes Medical Institute Investigators., European Project: 305762,HEALTH,FP7-HEALTH-2012-INNOVATION-1,HIT HIDDEN HIV(2012), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania [Philadelphia], Virus et Immunité - Virus and immunity, The Rockefeller University, Institut Pasteur [Paris], Virus et Immunité, Institut Pasteur [Paris] - Centre National de la Recherche Scientifique (CNRS), Princeton University [Pinceton], California Institute of Technology, and F.K. was supported by the Stavros Niarchos Foundation. E.B., M.D., A.P., and C.M.R. were supported by the Starr Foundation. O.S. is supported by grants from the Agence Nationale de Recherche sur le Sida, Sidaction, AREVA Foundation, Vaccine Research Institute, the Labex Integrative Biology of Emerging Infectious Diseases program, the Seventh Framework Programme HIT Hidden HIV (Health-F3-2012-305762), and Institut Pasteur. This work was supported in part by the Bill and Melinda Gates Foundation with Comprehensive Antibody Vaccine Immune Monitoring Consortium Grant 1032144 (to M.S.S.) and Collaboration for AIDS Vaccine Discovery Grants 38660 (to P.J.B.) and 38619s (to M.C.N.). This work was also supported by the German Center for Infection Research (S.G. and H.B.), UL1 TR000043 Translational Science Award (Clinical and Translational Science Award) program, AI 100663-01 (to M.C.N.), Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, and AI 100148-01 (to P.J.B. and M.C.N.). P.J.B. and M.C.N. are Howard Hughes Medical Institute Investigators.

Subjects
medicine.medical_treatment, [SDV]Life Sciences [q-bio], Human immunodeficiency virus (HIV), HIV Infections, Mice, Transgenic, Viremia, Real-Time Polymerase Chain Reaction, medicine.disease_cause, Virus, Mice, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Humans, DNA Primers, 030304 developmental biology, 0303 health sciences, glycan, Multidisciplinary, biology, CD4bs, Sequence Analysis, DNA, Single injection, Immunotherapy, Biological Sciences, Dependovirus, Viral Load, medicine.disease, Antibodies, Neutralizing, Virology, Antiretroviral therapy, 3. Good health, Anti-Retroviral Agents, gp160, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, 030220 oncology & carcinogenesis, DNA, Viral, Immunology, HIV-1, biology.protein, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Drug Therapy, Combination, Antibody, Viral load
Abstract

International audience; Effective control of HIV-1 infection in humans is achieved using combinations of antiretroviral therapy (ART) drugs. In humanized mice (hu-mice), control of viremia can be achieved using either ART or by immunotherapy using combinations of broadly neutralizing antibodies (bNAbs). Here we show that treatment of HIV-1-infected hu-mice with a combination of three highly potent bNAbs not only resulted in complete viremic control but also led to a reduction in cell-associated HIV-1 DNA. Moreover, lowering the initial viral load by coadministration of ART and immunotherapy enabled prolonged viremic control by a single bNAb after ART was withdrawn. Similarly, a single injection of adeno-associated virus directing expression of one bNAb produced durable viremic control after ART was terminated. We conclude that immunotherapy reduces plasma viral load and cell-associated HIV-1 DNA and that decreasing the initial viral load enables single bNAbs to control viremia in hu-mice.

Published
2013

38. Cross-Talk Between the Intestinal Epithelium and Salmonella Typhimurium

Author

Sandrine Ménard, Sonia Lacroix-Lamandé, Katrin Ehrhardt, Jin Yan, Guntram A. Grassl, Agnès Wiedemann, Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Infectiologie et Santé Publique (UMR ISP), Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), The Second Xiangya Hospital of Central South University [Hunan, China], Central South University [Changsha], France Région Occitanie/FEDER, Fondation Allemande pour la recherche (SFB900/3 - 158989968, TP08), Centre allemand de recherche sur les infections (DZIF), and Wiedemann, Agnès

Subjects
Microbiology (medical), [SDV] Life Sciences [q-bio], host defense, [SDV]Life Sciences [q-bio], gastrointestinal tract, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, bacteria, invasion, Microbiology, survival, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Abstract

Salmonella entericaserovars are invasive gram-negative bacteria, causing a wide range of diseases from gastroenteritis to typhoid fever, representing a public health threat around the world.Salmonellagains access to the intestinal lumen after oral ingestion of contaminated food or water. The crucial initial step to establish infection is the interaction with the intestinal epithelium. Human-adapted serovars such asS.Typhi orS.Paratyphi disseminate to systemic organs and induce life-threatening disease known as typhoid fever, whereas broad-host serovars such asS.Typhimurium usually are limited to the intestine and responsible for gastroenteritis in humans. To overcome intestinal epithelial barrier,Salmonelladeveloped mechanisms to induce cellular invasion, intracellular replication and to face host defence mechanisms. Depending on the serovar and the respective host organism, disease symptoms differ and are linked to the ability of the bacteria to manipulate the epithelial barrier for its own profit and cross the intestinal epithelium.This review will focus onS.Typhimurium (STm). To better understand STm pathogenesis, it is crucial to characterize the crosstalk between STm and the intestinal epithelium and decipher the mechanisms and epithelial cell types involved. Thus, the purpose of this review is to summarize our current knowledge on the molecular dialogue between STm and the various cell types constituting the intestinal epithelium with a focus on the mechanisms developed by STm to cross the intestinal epithelium and access to subepithelial or systemic sites and survive host defense mechanisms.

Published
2022

39. An early warning system for emerging SARS-CoV-2 variants

Author

Lorenzo Subissi, Anne von Gottberg, Lipi Thukral, Nathalie Worp, Bas B. Oude Munnink, Surabhi Rathore, Laith J. Abu-Raddad, Ximena Aguilera, Erik Alm, Brett N. Archer, Homa Attar Cohen, Amal Barakat, Wendy S. Barclay, Jinal N. Bhiman, Leon Caly, Meera Chand, Mark Chen, Ann Cullinane, Tulio de Oliveira, Christian Drosten, Julian Druce, Paul Effler, Ihab El Masry, Adama Faye, Simani Gaseitsiwe, Elodie Ghedin, Rebecca Grant, Bart L. Haagmans, Belinda L. Herring, Shilpa S. Iyer, Zyleen Kassamali, Manish Kakkar, Rebecca J. Kondor, Juliana A. Leite, Yee-Sin Leo, Gabriel M. Leung, Marco Marklewitz, Sikhulile Moyo, Jairo Mendez-Rico, Nada M. Melhem, Vincent Munster, Karen Nahapetyan, Djin-Ye Oh, Boris I. Pavlin, Thomas P. Peacock, Malik Peiris, Zhibin Peng, Leo L. M. Poon, Andrew Rambaut, Jilian Sacks, Yinzhong Shen, Marilda M. Siqueira, Sofonias K. Tessema, Erik M. Volz, Volker Thiel, Sylvie van der Werf, Sylvie Briand, Mark D. Perkins, Maria D. Van Kerkhove, Marion P. G. Koopmans, Anurag Agrawal, World Health Organisation (WHO), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), National Institute for Communicable Diseases [Johannesburg] (NICD), University of the Witwatersrand [Johannesburg] (WITS), Central Scientific Instruments Organisation (CSIR), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Weill Cornell Medicine [Qatar], Universidad del Desarollo [Santiago, Chile] (UDD), European Centre for Disease Prevention and Control [Stockholm, Sweden] (ECDC), WHO - Regional Office for the Eastern Mediterranean [Cairo, Egypt] (EMRO), Imperial College London, Victorian Infectious Diseases Reference Laboratory [Melbourne, Australia] (VIDRL), UK Health Security Agency [London] (UKHSA), World Organisation for Animal Health (WOAH), Stellenbosch University, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Infection Research, Partnersite Munich (DZIF), The University of Western Australia (UWA), Food and Agriculture Organization of the United Nations [Rome, Italie] (FAO), Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD), Botswana Harvard AIDS Institute Partnership, Harvard T.H. Chan School of Public Health, National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), World Health Organization [Kinshasa, Democratic Republic of Congo] (WHO-DRC), United States Centers for Disease Control and Prevention, The University of Hong Kong (HKU), American University of Beirut [Beyrouth] (AUB), Robert Koch Institute [Berlin] (RKI), Chinese Center for Disease Control and Prevention, University of Edinburgh, Fudan University [Shanghai], Instituto Oswaldo Cruz / Oswaldo Cruz Institute [Rio de Janeiro] (IOC), Fundação Oswaldo Cruz / Oswaldo Cruz Foundation (FIOCRUZ), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centers for Disease Control and Prevention [Pretoria, South Africa] (CDC-South Africa), Centers for Disease Control and Prevention (CDC), University of Bern, Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR - laboratoire coordonnateur), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Ashoka University, We acknowledge scientists, public health professionals and Ministries of Health across the world for early generation and sharing of data on SARS-CoV-2 variants., and Virology

Subjects
630 Agriculture, SARS-CoV-2, [SDV]Life Sciences [q-bio], COVID-19, Humans, General Medicine, General Biochemistry, Genetics and Molecular Biology
Abstract

International audience

Published
2022

40. Rifapentine access in Europe:growing concerns over key tuberculosis treatment component

Author

Lorenzo Guglielmetti, Gunar Günther, Claude Leu, Daniela Cirillo, Raquel Duarte, Alberto L. Garcia-Basteiro, Delia Goletti, Mateja Jankovic, Liga Kuksa, Florian P. Maurer, Frédéric Méchaï, Simon Tiberi, Frank van Leth, Nicolas Veziris, Christoph Lange, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Avicenne [AP-HP], Centre National de Référence des Mycobactéries et de la Résistance aux Antituberculeux [CHU Pitié-Salpêtrière] (CNR-MyRMA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Bern, University of Namibia (UNAM), IRCCS San Raffaele Scientific Institute [Milan, Italie], Universidade do Porto = University of Porto, Directorate-General of Health [Lisbonne], Centro de Investigação em Saúde de Manhiça [Maputo, Mozambique] (CISM), Universitat de Barcelona (UB), National Institute for Infectious Diseases 'Lazzaro Spallanzani', Zagreb School of Medicine [Zagreb, Croatia] (Dubrava University Hospital), University of Zagreb, Riga East University Hospital, Riga Stradins University (RSU), Forschungszentrum Borstel - Research Center Borstel, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), German Center for Infection Research - Partner Site Hamburg-Lübeck-Borstel-Riems, German Centre for Infection Research (DZIF), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)-Université Sorbonne Paris Nord, Queen Mary University of London (QMUL), Royal Free Hospital [London, UK], Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), Amsterdam Public Health Research Institute [The Netherlands], CHU Saint-Antoine [AP-HP], Universität zu Lübeck = University of Lübeck [Lübeck], Baylor College of Medicine (BCM), Baylor University, Study Group on Mycobacteria of the European Society of Microbiology and Infectious Diseases (ESGMYC), European Society of Mycobacteriology (ESM), European Respiratory Society (ERS) and, Tuberculosis Network European Trials group (TBnet), Health Economics and Health Technology Assessment, APH - Global Health, and APH - Methodology

Subjects
Pulmonary and Respiratory Medicine, Antitubercular Agents/therapeutic use, Antitubercular Agents, Tuberculosis / epidemiology, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Drug Therapy, SDG 3 - Good Health and Well-being, Antibiotics, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Antibiotics, Antitubercular* / therapeutic use, Tuberculosis, Humans, Rifampin / analogs & derivatives, 610 Medicine & health, Antibiotics, Antitubercular, Antitubercular Agents / therapeutic use, Tuberculosis/drug therapy, Tuberculosis / drug therapy, Rifampin/analogs & derivatives, Antitubercular/therapeutic use, rifapentine, tuberculosis, Europe, Combination, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Drug Therapy, Combination, Rifampin, Rifampin / therapeutic use, Antibiotics, Antitubercular/therapeutic use
Abstract

International audience; Rifapentine, a synthetic derivate of rifampicin which was developed in 1965, has interesting pharmacological properties, including a long terminal half-life (13 h, compared to 2-3 h for rifampicin) and promising bactericidal activity against Mycobacterium tuberculosis. Despite being approved in 1998 by the US Food and Drug Administration (FDA) for the treatment of pulmonary tuberculosis, its global use has been limited by unavailability. In the past decade, new evidence has emerged to define rifapentine as a key component for treatment of active disease and latent infection with M. tuberculosis (LTBI).

Published
2022

41. Hypoxia inducible factors regulate hepatitis B virus replication by activating the basal core promoter

Author

Valentina D'Arienzo, David R. Mole, Luis Nobre, Helene Borrmann, Ulrike Protzer, James M. Harris, Ester M. Hammond, Thomas F. Baumert, Laurent Mailly, Jochen M. Wettengel, Peter Balfe, Rosalba Minisini, Mathias Heikenwalder, Jane A. McKeating, Tobias Riedl, Peter Jianrui Liu, Peter A C Wing, Nicholas R. Frampton, Xiaodong Zhuang, Mario Pirisi, Michael P. Weekes, Thomas Michler, Andrea Magri, univOAK, Archive ouverte, University of Oxford, German Center for Infection Research, Partnersite Munich (DZIF), Università degli Studi del Piemonte Orientale - Amedeo Avogadro (UPO), University of Birmingham [Birmingham], Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), and University of Cambridge [UK] (CAM)

Subjects
Transcriptional Activation, 0301 basic medicine, Hepatitis B virus, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Hepadnaviridae, Virus Replication, medicine.disease_cause, Virus, Hypoxia-Inducible Factor-Proline Dioxygenases, 03 medical and health sciences, Hepatitis B, Chronic, 0302 clinical medicine, Kruppel-Like Factor 6, medicine, Animals, HIF, Humans, Anaerobiosis, Hypoxia-Responsive Elements, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Host Microbial Interactions, Hepatology, biology, hypoxia, Liver cell, biology.organism_classification, Hepatitis B, ddc, Cell biology, Oxygen tension, Oxygen, 030104 developmental biology, Cellular Microenvironment, Liver, Viral replication, Hypoxia-inducible factors, 030211 gastroenterology & hepatology, Hypoxia-Inducible Factor 1, transcription, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Signal Transduction, Research Article
Abstract

Background & Aims Hypoxia inducible factors (HIFs) are a hallmark of inflammation and are key regulators of hepatic immunity and metabolism, yet their role in HBV replication is poorly defined. HBV replicates in hepatocytes within the liver, a naturally hypoxic organ, however most studies of viral replication are performed under conditions of atmospheric oxygen, where HIFs are inactive. We therefore investigated the role of HIFs in regulating HBV replication. Methods Using cell culture, animal models, human tissue and pharmacological agents inhibiting the HIF-prolyl hydroxylases, we investigated the impact of hypoxia on the HBV life cycle. Results Culturing liver cell-based model systems under low oxygen uncovered a new role for HIFs in binding HBV DNA and activating the basal core promoter, leading to increased pre-genomic RNA and de novo HBV particle secretion. The presence of hypoxia responsive elements among all primate members of the hepadnaviridae highlights an evolutionary conserved role for HIFs in regulating this virus family. Conclusions Identifying a role for this conserved oxygen sensor in regulating HBV transcription suggests that this virus has evolved to exploit the HIF signaling pathway to persist in the low oxygen environment of the liver. Our studies show the importance of considering oxygen availability when studying HBV-host interactions and provide innovative routes to better understand and target chronic HBV infection. Lay summary Viral replication in host cells is defined by the cellular microenvironment and one key factor is local oxygen tension. Hepatitis B virus (HBV) replicates in the liver, a naturally hypoxic organ. Hypoxia inducible factors (HIFs) are the major sensors of low oxygen; herein, we identify a new role for these factors in regulating HBV replication, revealing new therapeutic targets., Graphical abstract, Highlights • Primate hepadnaviridae encode conserved hypoxia response elements. • Hypoxia inducible factors bind HBV DNA and activate the basal core promoter. • Pharmacological stabilization of hypoxia inducible factors and low oxygen increases HBV transcription and particle genesis. • Knockdown studies show a role for both HIF-1α and HIF-2α in regulating HBV transcription.

Published
2021

42. Critical Assessment of Metagenome Interpretation: the second round of challenges

Author

Fernando Meyer, Adrian Fritz, Zhi-Luo Deng, David Koslicki, Till Robin Lesker, Alexey Gurevich, Gary Robertson, Mohammed Alser, Dmitry Antipov, Francesco Beghini, Denis Bertrand, Jaqueline J. Brito, C. Titus Brown, Jan Buchmann, Aydin Buluç, Bo Chen, Rayan Chikhi, Philip T. L. C. Clausen, Alexandru Cristian, Piotr Wojciech Dabrowski, Aaron E. Darling, Rob Egan, Eleazar Eskin, Evangelos Georganas, Eugene Goltsman, Melissa A. Gray, Lars Hestbjerg Hansen, Steven Hofmeyr, Pingqin Huang, Luiz Irber, Huijue Jia, Tue Sparholt Jørgensen, Silas D. Kieser, Terje Klemetsen, Axel Kola, Mikhail Kolmogorov, Anton Korobeynikov, Jason Kwan, Nathan LaPierre, Claire Lemaitre, Chenhao Li, Antoine Limasset, Fabio Malcher-Miranda, Serghei Mangul, Vanessa R. Marcelino, Camille Marchet, Pierre Marijon, Dmitry Meleshko, Daniel R. Mende, Alessio Milanese, Niranjan Nagarajan, Jakob Nissen, Sergey Nurk, Leonid Oliker, Lucas Paoli, Pierre Peterlongo, Vitor C. Piro, Jacob S. Porter, Simon Rasmussen, Evan R. Rees, Knut Reinert, Bernhard Renard, Espen Mikal Robertsen, Gail L. Rosen, Hans-Joachim Ruscheweyh, Varuni Sarwal, Nicola Segata, Enrico Seiler, Lizhen Shi, Fengzhu Sun, Shinichi Sunagawa, Søren Johannes Sørensen, Ashleigh Thomas, Chengxuan Tong, Mirko Trajkovski, Julien Tremblay, Gherman Uritskiy, Riccardo Vicedomini, Zhengyang Wang, Ziye Wang, Zhong Wang, Andrew Warren, Nils Peder Willassen, Katherine Yelick, Ronghui You, Georg Zeller, Zhengqiao Zhao, Shanfeng Zhu, Jie Zhu, Ruben Garrido-Oter, Petra Gastmeier, Stephane Hacquard, Susanne Häußler, Ariane Khaledi, Friederike Maechler, Fantin Mesny, Simona Radutoiu, Paul Schulze-Lefert, Nathiana Smit, Till Strowig, Andreas Bremges, Alexander Sczyrba, Alice Carolyn McHardy, Braunschweig Integrated Centre of Systems Biology [Braunschweig] (BRICS), Technische Universität Braunschweig = Technical University of Braunschweig [Braunschweig]-Helmholtz Centre for Infection Research (HZI), Pennsylvania State University (Penn State), Penn State System, German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), Saint Petersburg State University (SPBU), Department of Information Technology and Electrical Engineering [Zürich] (D-ITET), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Center for Algorithmic Biotechnology [Saint Petersburg], Institute of Translational Biomedicine [Saint-Petersburg], Saint Petersburg University (SPBU)-Saint Petersburg University (SPBU), Centre for Integrative Biology (CIBIO), University of Trento (CIBIO), University of Trento [Trento], Genome Institute of Singapore (GIS), University of Southern California (USC), University of California [Davis] (UC Davis), University of California (UC), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Lawrence Berkeley National Laboratory [Berkeley] (LBNL), Institut Pasteur [Paris] (IP), National Food Institute [Lyngby] (Forside), Drexel University, Robert Koch Institute [Berlin] (RKI), University of Technology Sydney (UTS), DOE Joint Genome Institute [Walnut Creek], University of California [Los Angeles] (UCLA), Intel Corporation [Santa Clara], Intel Corporation [USA], Department of Plant and Environmental Sciences [Frederiksberg], University of Copenhagen = Københavns Universitet (UCPH), Fudan University [Shanghai], Beijing Genomics Institute [Shenzhen] (BGI), Novo Nordisk Foundation Center for Biosustainability, Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Université de Genève = University of Geneva (UNIGE), The Arctic University of Norway [Tromsø, Norway] (UiT), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], University of California [San Diego] (UC San Diego), University of Wisconsin-Madison, Scalable, Optimized and Parallel Algorithms for Genomics (GenScale), Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-GESTION DES DONNÉES ET DE LA CONNAISSANCE (IRISA-D7), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Informatique, Signal et Automatique de Lille - UMR 9189 (CRIStAL), Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Hasso Plattner Institute [Potsdam, Germany], The University of Sydney, Inria Lille - Nord Europe, Institut National de Recherche en Informatique et en Automatique (Inria), Amsterdam UMC - Amsterdam University Medical Center, Structural and Computational Biology, European Molecular Biology Laboratory [Heidelberg] (EMBL), DTU Electrical Engineering [Lyngby], National Institutes of Health [Bethesda] (NIH), Department of Biology [ETH Zürich] (D-BIOL), University of Virginia, IT University of Copenhagen (ITU), Freie Universität Berlin, University of Potsdam = Universität Potsdam, Florida International University [Miami] (FIU), National Research Council of Canada (NRC), Phase Genomics [Seattle], Max Planck Institute for Plant Breeding Research (MPIPZ), Helmholtz Centre for Infection Research (HZI), Aarhus University [Aarhus], Center for Biotechnology (CeBiTec), Universität Bielefeld = Bielefeld University, Open access funding provided by Helmholtz-Zentrum für Infektionsforschung GmbH (HZI), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), and Medical Microbiology and Infection Prevention

Subjects
06 Biological Sciences, 10 Technology, 11 Medical and Health Sciences, Reproducibility of Results, Cell Biology, DNA, Sequence Analysis, DNA, Biochemistry, Archaea, Software, Metagenome, Metagenomics, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Molecular Biology, Sequence Analysis, Biotechnology, Developmental Biology
Abstract

Evaluating metagenomic software is key for optimizing metagenome interpretation and focus of the Initiative for the Critical Assessment of Metagenome Interpretation (CAMI). The CAMI II challenge engaged the community to assess methods on realistic and complex datasets with long- and short-read sequences, created computationally from around 1,700 new and known genomes, as well as 600 new plasmids and viruses. Here we analyze 5,002 results by 76 program versions. Substantial improvements were seen in assembly, some due to long-read data. Related strains still were challenging for assembly and genome recovery through binning, as was assembly quality for the latter. Profilers markedly matured, with taxon profilers and binners excelling at higher bacterial ranks, but underperforming for viruses and Archaea. Clinical pathogen detection results revealed a need to improve reproducibility. Runtime and memory usage analyses identified efficient programs, including top performers with other metrics. The results identify challenges and guide researchers in selecting methods for analyses., Nature Methods, 19 (8), ISSN:1548-7105, ISSN:1548-7091

Published
2022

43. Zika Virus Circulation in Mali

Author

Abdoulaye Dabo, Simon Cauchemez, Souleymane Sacko, Bourema Kouriba, Abdoulaye Djimde, Jan Felix Drexler, Anna-Bella Failloux, Pierre Gallian, Abdoul Karim Sangaré, Ogobara K. Doumbo, Issa Diarra, Drissa Coulibaly, Amatigue Zeguime, Xavier de Lamballerie, Nathanaël Hozé, Elif Nurtop, Bakary Fofana, Boris Pastorino, Stéphane Priet, Issaka Sagara, Mahamadou Ali Thera, Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Malaria Research and Training Center [Bamako, Mali], Université de Bamako, Ministère de la Santé et des Affaires Sociales du Mali [Bamako, Mali], Université des Sciences, des Techniques et des Technologies de Bamako (USTTB), Etablissement Français du Sang - Alpes-Méditerranée (EFS - Alpes-Méditerranée), Etablissement Français du Sang, German Center for Infection Research, Partnersite Munich (DZIF), Arbovirus et Insectes Vecteurs - Arboviruses and Insect Vectors, Institut Pasteur [Paris] (IP), Modélisation mathématique des maladies infectieuses - Mathematical modelling of Infectious Diseases, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), BUISINE, Soline, Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université des sciences, des techniques et des technologies de Bamako (USTTB), Institut Pasteur [Paris], and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
Microbiology (medical), Male, Epidemiology, 030231 tropical medicine, Population, vector-borne infections, lcsh:Medicine, Blood Donors, Zika Virus Circulation in Mali, Mali, Asymptomatic, Arbovirus, lcsh:Infectious and parasitic diseases, Zika virus, Serology, 03 medical and health sciences, 0302 clinical medicine, Seroepidemiologic Studies, medicine, Seroprevalence, Humans, lcsh:RC109-216, viruses, 030212 general & internal medicine, education, mosquitoes, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, education.field_of_study, biology, seroprevalence, Transmission (medicine), Zika Virus Infection, Research, lcsh:R, Outbreak, Zika Virus, biology.organism_classification, medicine.disease, Virology, 3. Good health, Infectious Diseases, arbovirus, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, medicine.symptom
Abstract

International audience; The circulation of Zika virus (ZIKV) in Mali has not been clearly characterized. Therefore, we conducted a serologic survey of 793 asymptomatic volunteers >15 years of age (2016), and 637 blood donors (2013) to assess the seroprevalence of ZIKV infection in 2 ecoclimatic regions of Mali, tropical savannah and warm semiarid region, using ELISA and seroneutralization assays. The overall seroprevalence was ≈12% and increased with age, with no statistical difference between male and female participants. In the warm semiarid study sites we detected immunological markers of an outbreak that occurred in the late 1990s in 18% (95% CI 13%-23%) of participants. In tropical savannah sites, we estimated a low rate of endemic transmission, with 2.5% (95% CI 2.0%-3.1%) of population infected by ZIKV annually. These data demonstrate the circulation of ZIKV in Mali and provide evidence of a previously unidentified outbreak that occurred in the late 1990s.

Published
2020

44. NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Author

Stephan Spahn, Florian Müller, Revant Gupta, Dominik Pfister, Kornelius Schulze, Pierre Bedossa, Eleni Kotsiliti, Lars Zender, Mathias Heikenwalder, Nicolás Gonzalo Núñez, Peter Schirmacher, Axel Schulz, Jan Kosla, Adrian T. Billeter, Thomas Engleitner, Aleksandra Deczkowska, Danijela Heide, Donato Inverso, Susanne Roth, Olivier Govaere, Carla Montironi, Martha M. Kirstein, Dan G. Duda, Antonio D'Alessio, Jörn M. Schattenberg, Ekaterina Friebel, Tiziana Pressiani, F. Hucke, Jörg Trojan, Michael Bitzer, Suhail Yousuf, Bernhard Scheiner, Marina Ruiz de Galarreta, Markus Peck-Radosavljevic, Michael Allison, Nuh N. Rahbari, Simon Cockell, Brinda Emu, Ahmed Kaseb, David J. Pinato, Matthias P. Ebert, Joachim C. Mertens, Jean-François Dufour, Fabian Rössler, Achim Weber, Katharina Wolter, Thomas Decaens, Amaia Lujambio, Anja Moncsek, Daniela Lenggenhager, Katharina Pomej, Nisar P. Malek, Fabian Finkelmeier, Elisabetta Bugianesi, Valentina Leone, Ann K. Daly, Michael Dudek, Manfred Claassen, Zuzana Macek Jilkova, Henning Wege, Florian Castet, Marta Szydlowska, Beat P. Müller-Stich, Ramy Younes, Nicola Personeni, Philipp K. Haber, Marco Bueter, Manfred Jugold, Andrea Schietinger, Hiroto Kikuchi, Ido Amit, Sandra Koch, Dina Tiniakos, Ana Teijeiro, Jan-Philipp Mallm, Josep M. Llovet, Indrabahadur Singh, Percy A. Knolle, Sara De Dosso, Roland Rad, Arndt Vogel, Henrik E. Mei, Burkhard Becher, Nabil Djouder, Tom Luedde, Felix Meissner, Oliver Waidmann, Parice N. Marche, Viktor Umansky, Hellmut G. Augustin, Thomas U. Marron, Matthias Pinter, Mengjie Qiu, Arndt Weinmann, Ankit Sinha, Kristian Unger, Assaf Weiner, Vlad Ratziu, Quentin M. Anstee, Kristin Stirm, Yi Hsiang Huang, Alexander Siebenhüner, Fabian Kütting, Lorenza Rimassa, Dirk Waldschmidt, Masatoshi Kudo, Marc Ringelhan, Michele Vacca, Roser Pinyol, Fabio Marra, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Novo Nordisk A/S [Maløv, Denmark], Universität Zürich [Zürich] = University of Zurich (UZH), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Newcastle University [Newcastle], Medizinische Universität Wien = Medical University of Vienna, University of Tübingen, UniversitätsKlinikum Heidelberg, Weizmann Institute of Science [Rehovot, Israël], Max Planck Institute of Biochemistry (MPIB), Max-Planck-Gesellschaft, Technical University of Munich (TUM), University hospital of Zurich [Zurich], Helmholtz-Zentrum München (HZM), Heidelberg University, Spanish National Cancer Research Center (CNIO), Icahn School of Medicine at Mount Sinai [New York] (MSSM), National and Kapodistrian University of Athens (NKUA), University of Turin, Addenbrooke's Hospital, Cambridge University NHS Trust, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), University Medical Center [Mainz], Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Istituto Clinico Humanitas [Milan] (IRCCS Milan), Humanitas University [Milan] (Hunimed), Hannover Medical School [Hannover] (MHH), University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Klinikum Klagenfurt am Wörthersee, Universitätsklinikum Frankfurt, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Oncology Institute of Southern Switzerland (IOSI), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Memorial Sloane Kettering Cancer Center [New York], Weill Medical College of Cornell University [New York], Heidelberg University Hospital [Heidelberg], Medical Faculty [Mannheim], Massachusetts General Hospital [Boston], University of Cologne, Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, German Center for Infection Research, Partnersite Munich (DZIF), University Medical Center [Tubingen, Germany], Inselspital Bern, University of Bern, The University of Texas M.D. Anderson Cancer Center [Houston], Kindai University, National Yang Ming University (NYMU), Taipei Veterans General Hospital [Taiwan], Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Eberhard Karls University [Tübingen, Germany], Université Grenoble Alpes (UGA), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), CHU Grenoble, Hammersmith Hospital NHS Imperial College Healthcare, Università degli Studi del Piemonte Orientale - Amedeo Avogadro (UPO), Institució Catalana de Recerca i Estudis Avançats (ICREA), Pfister, Dominik [0000-0002-0542-2638], Núñez, Nicolás Gonzalo [0000-0003-3837-270X], Govaere, Olivier [0000-0002-4426-6930], Szydlowska, Marta [0000-0002-4660-899X], Gupta, Revant [0000-0002-0881-5074], Deczkowska, Aleksandra [0000-0003-0844-4346], Friebel, Ekaterina [0000-0003-1419-2376], Lenggenhager, Daniela [0000-0002-5382-9854], Moncsek, Anja [0000-0002-1191-5842], Inverso, Donato [0000-0003-0987-3345], Vacca, Michele [0000-0002-1973-224X], Marra, Fabio [0000-0001-8629-0878], Allison, Michael [0000-0003-3677-3294], D'Alessio, Antonio [0000-0002-9164-3671], Personeni, Nicola [0000-0002-7995-272X], Rimassa, Lorenza [0000-0001-9957-3615], Pomej, Katharina [0000-0002-2807-3565], Peck-Radosavljevic, Markus [0000-0002-0597-2728], Mallm, Jan-Philipp [0000-0002-7059-4030], Schietinger, Andrea [0000-0003-3644-1687], Augustin, Hellmut G [0000-0002-7173-4242], Kikuchi, Hiroto [0000-0002-3601-8435], Duda, Dan G [0000-0001-7065-8797], Mei, Henrik E [0000-0003-0697-7755], Schulz, Axel Ronald [0000-0002-5106-0148], Ringelhan, Marc [0000-0003-3131-5657], Lujambio, Amaia [0000-0002-2798-1481], Dufour, Jean-Francois [0000-0002-8062-1346], Kudo, Masatoshi [0000-0002-4102-3474], Djouder, Nabil [0000-0001-8423-1030], Zender, Lars [0000-0001-7626-2849], Pinato, David J [0000-0002-3529-0103], Rad, Roland [0000-0002-6849-9659], Mertens, Joachim C [0000-0003-2007-0308], Weber, Achim [0000-0003-0073-3637], Meissner, Felix [0000-0003-1000-7989], Amit, Ido [0000-0003-2968-877X], Knolle, Percy [0000-0003-2983-0414], Becher, Burkhard [0000-0002-1541-7867], Llovet, Josep M [0000-0003-0547-2667], Heikenwalder, Mathias [0000-0002-3135-2274], Apollo - University of Cambridge Repository, Max-Planck-Institut für Biochemie = Max Planck Institute of Biochemistry (MPIB), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz Zentrum München = German Research Center for Environmental Health, Università degli studi di Torino = University of Turin (UNITO), Università degli Studi di Firenze = University of Florence (UniFI), MARCHE, Patrice, D’Alessio, Antonio [0000-0002-9164-3671], Augustin, Hellmut G. [0000-0002-7173-4242], Duda, Dan G. [0000-0001-7065-8797], Mei, Henrik E. [0000-0003-0697-7755], Pinato, David J. [0000-0002-3529-0103], Mertens, Joachim C. [0000-0003-2007-0308], and Llovet, Josep M. [0000-0003-0547-2667]

Subjects
Male, Carcinogenesis, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Programmed Cell Death 1 Receptor, CD8-Positive T-Lymphocytes, B7-H1 Antigen, 13/2, 13/1, Mice, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, LIVER-CANCER, R PACKAGE, RNA-SEQ, 14/19, Cancer, 0303 health sciences, Multidisciplinary, NONALCOHOLIC STEATOHEPATITIS, Liver Neoplasms, article, ddc, 3. Good health, 13/31, Multidisciplinary Sciences, medicine.anatomical_structure, Liver, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Disease Progression, Science & Technology - Other Topics, [SDV.IMM]Life Sciences [q-bio]/Immunology, 64/60, Tumor necrosis factor alpha, Immunotherapy, Adjuvant, 631/67, Carcinoma, Hepatocellular, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, 610 Medicine & health, [SDV.CAN]Life Sciences [q-bio]/Cancer, 14/32, 03 medical and health sciences, 14/34, 13/21, [SDV.CAN] Life Sciences [q-bio]/Cancer, ADVANCED HEPATOCELLULAR-CARCINOMA, NAFLD, medicine, Animals, Humans, 14/35, 030304 developmental biology, Science & Technology, Tumor Necrosis Factor-alpha, business.industry, 631/250/251, medicine.disease, PHASE-III, digestive system diseases, 13/51, 14/63, 59/57, T-CELLS, Cancer research, Steatohepatitis, business, CD8
Abstract

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1–5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH–HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH–HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH–HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment., In hepatocellular carcinoma driven by non-alcoholic steatohepatitis, aberrant T cell activation and impaired immune surveillance seem to make hepatocellular carcinoma less responsive to anti-PD1 or anti-PDL1 immunotherapy.

Published
2021

45. At least seven distinct rotavirus genotype constellations in bats with evidence of reassortment and zoonotic transmissions

Author

Ceren Simsek, Alexander N. Lukashev, Ward Deboutte, Yaw Adu Sarkodie, Daan Jansen, Hermann Ulrich Everling, Kwe Claude Yinda, Tabea Binger, Florian Gloza-Rausch, Eric M. Leroy, Mathieu Bourgarel, Leen Beller, Victor M. Corman, Augustina Sylverken, Stoian Yordanov, Marc Van Ranst, Jan Felix Drexler, Samuel Oppong, Gael Darren Maganga, Jelle Matthijnssens, Peter Vallo, Christian Drosten, Antje Seebens-Hoyer, Andrea Rasche, Rega Institute for Medical Research [Leuven, België], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Infection Research, Partnersite Munich (DZIF), University of Bonn, Sechenov First Moscow State Medical University, Université des Sciences et Techniques de Masuku [Franceville, Gabon] (USTM), Centre International de Recherches Médicales de Franceville (CIRMF), Kumasi Centre for Collaborative Research in Tropical Medicine (KCCR), Noctalis, Centre for Bat Protection and Information, Forestry Board Directorate of Strandja Natural Park, Strandja Natural Park, Kwame Nkrumah University of Science and Technology [GHANA] (KNUST), Institute of Vertebrate Biology of the Czech Academy of Sciences (IVB / CAS), Czech Academy of Sciences [Prague] (CAS), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Animal, Santé, Territoires, Risques et Ecosystèmes (UMR ASTRE), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Département Systèmes Biologiques (Cirad-BIOS), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), This project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie agreement no. 721367 granted to J.F.D., J.M., and M.V.R. EU Horizon 2020 projects EVAg (grant agreement number 653316) and COMPARE (agreement number 643476) granted to C.D., and the Russian Science Foundation grant 19-15-00055 to A.N.L. also provided funding to the current study. H.U.E. had a personal scholarship from the BONFOR intramural program at the University of Bonn. German Federal Ministry of Education and Research (BMBF) (project code 01KIO16D), Deutsche Forschungsgemeinschaft (DFG DR 772-3/1), Deutsche Forschungsgemeinschaft within the Africa Infectious Diseases program gave grants to C.D. and Y.A.S. (DR 772/3-1) and to S.O. (KA1241/18-1) that were also among the funding contributions. A personal scholarship granted to A.R. from the German Academic Exchange Service (DAAD) supported field work in Costa Rica. D. J. was supported by the Fonds Wetenschappelijk Onderzoek (Research foundation Flanders) (1S78019N). L.B. was supported by the Fonds Wetenschappelijk Onderzoek (1S61618N). K.C.Y. was funded by the Interfaculty Council for Development Cooperation (IRO) from the KU Leuven. The computing power in this work was provided by the VSC (Flemish Supercomputer Centre), financed by the FWO and the Flemish government, department EWI., European Project: 777657,H2020-EU.1.3.3. - Stimulating innovation by means of cross-fertilisation of knowledge,777657,MSCA-RISE(2018), European Project: 653316,H2020,H2020-INFRAIA-2014-2015,EVAg(2015), European Project: 643476,H2020,H2020-PHC-2014-single-stage,COMPARE(2014), Universität Bonn = University of Bonn, Université des Sciences et Techniques de Masuku (USTM), and Kwame Nkrumah University of Science and Technology (KNUST)

Subjects
Rotavirus, Viral metagenomics, [SDV]Life Sciences [q-bio], viruses, Reassortment, medicine.disease_cause, L73 - Maladies des animaux, Genome, Zoonoses, Chiroptera, Genotype, Phylogeny, 0303 health sciences, Phylogenetic tree, Strain (biology), [SDV.BA]Life Sciences [q-bio]/Animal biology, Zoonosis, virus diseases, QR1-502, 3. Good health, S50 - Santé humaine, Middle East Respiratory Syndrome Coronavirus, Research Article, Diarrhea, zoonose, Middle East respiratory syndrome coronavirus, relation homme-faune, Genome, Viral, Ecological and Evolutionary Science, Biology, Microbiology, Rotavirus Infections, rotavirus genetic diversity, SA11, 03 medical and health sciences, Coronavirus 2 du syndrome respiratoire aigu sévère, Virology, medicine, Animals, Humans, Horses, Transmission des maladies, 030304 developmental biology, Genetic diversity, 030306 microbiology, SARS-CoV-2, COVID-19, Genetic Variation, zoonosis, medicine.disease, respiratory tract diseases, Evolutionary biology, bat rotavirus, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Metagenomics, Virus pathogène
Abstract

The increased research on bat coronaviruses after severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) allowed the very rapid identification of SARS-CoV-2. This is an excellent example of the importance of knowing viruses harbored by wildlife in general, and bats in particular, for global preparedness against emerging viral pathogens., Bats host many viruses pathogenic to humans, and increasing evidence suggests that rotavirus A (RVA) also belongs to this list. Rotaviruses cause diarrheal disease in many mammals and birds, and their segmented genomes allow them to reassort and increase their genetic diversity. Eighteen out of 2,142 bat fecal samples (0.8%) collected from Europe, Central America, and Africa were PCR-positive for RVA, and 11 of those were fully characterized using viral metagenomics. Upon contrasting their genomes with publicly available data, at least 7 distinct bat RVA genotype constellations (GCs) were identified, which included evidence of reassortments and 6 novel genotypes. Some of these constellations are spread across the world, whereas others appear to be geographically restricted. Our analyses also suggest that several unusual human and equine RVA strains might be of bat RVA origin, based on their phylogenetic clustering, despite various levels of nucleotide sequence identities between them. Although SA11 is one of the most widely used reference strains for RVA research and forms the backbone of a reverse genetics system, its origin remained enigmatic. Remarkably, the majority of the genotypes of SA11-like strains were shared with Gabonese bat RVAs, suggesting a potential common origin. Overall, our findings suggest an underexplored genetic diversity of RVAs in bats, which is likely only the tip of the iceberg. Increasing contact between humans and bat wildlife will further increase the zoonosis risk, which warrants closer attention to these viruses.

Published
2021

46. Modulation of alternative splicing during early infection of human primary B lymphocytes with Epstein-Barr virus (EBV): a novel function for the viral EBNA-LP protein

Author

Paulina Mrozek-Gorska, Fabrice Mure, Wolfgang Hammerschmidt, Didier Auboeuf, Florian Roisné-Hamelin, Evelyne Manet, Henri Gruffat, Hélène Polvèche, Manet, Evelyne, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des cellules souches pour le traitement et l'étude des maladies monogéniques (I-STEM), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, German Center for Infection Research [Heidelberg, Germany] (DZIF), Heidelberg University, Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Herpesvirus 4, Human, AcademicSubjects/SCI00010, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, medicine.disease_cause, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Virus, 03 medical and health sciences, Exon, Viral Proteins, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Genetics, medicine, RNA and RNA-protein complexes, Humans, Cells, Cultured, 030304 developmental biology, Regulation of gene expression, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0303 health sciences, Messenger RNA, B-Lymphocytes, Alternative splicing, Membrane Proteins, RNA-Binding Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Exons, Epstein–Barr virus, 3. Good health, Cell biology, Alternative Splicing, 030220 oncology & carcinogenesis, RNA splicing, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, NUMB, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, RNA Splice Sites
Abstract

Epstein-Barr virus (EBV) is a human herpesvirus associated with human cancers worldwide. Ex vivo, the virus efficiently infects resting human B lymphocytes and induces their continuous proliferation. This process is accompanied by a global reprogramming of cellular gene transcription. However, very little is known on the impact of EBV infection on the regulation of alternative splicing, a pivotal mechanism that plays an essential role in cell fate determination and is often deregulated in cancer. In this study, we have developed a systematic time-resolved analysis of cellular mRNA splice variant expression during EBV infection of resting B lymphocytes. Our results reveal that major modifications of alternative splice variant expression appear as early as day 1 post-infection and suggest that splicing regulation provides—besides transcription—an additional mechanism of gene expression regulation at the onset of B cell activation and proliferation. We also report a role for the viral proteins, EBNA2 and EBNA-LP, in the modulation of specific alternative splicing events and reveal a previously unknown function for EBNA-LP—together with the RBM4 splicing factor—in the alternative splicing regulation of two important modulators of cell proliferation and apoptosis respectively, NUMB and BCL-X.

Published
2021

47. Resurgence of Ebola Virus in 2021 in Guinea Suggests a New Paradigm for Outbreaks

Author

Fodé B. Sako, Jacob Camara, Amadou A. Sall, Ariane Düx, Giuditta Annibaldis, Meike Pahlmann, Abdoulaye Toure, Ousmane Faye, Mamadou Condé, Haby Diallo, Steven T. Pullan, Amadou Sidibe, Moriba Povogui, Fara Raymond Koundouno, Christophe Peyrefitte, Liana E. Kafetzopoulou, Alpha Kabinet Keita, Saa L. Millimono, Mandiou Diakite, Ahmadou Doré, Karla Pietro, N'. Faly Magassouba, Fabian H. Leendertz, Nicole Vidal, Stephan Günther, Anke Thielebein, Julia Hinzmann, Dembo Diakite, Ahidjo Ayouba, Cheikh Loucoubar, Kaka Kourouma, Martin Faye, Philippe Lemey, Moussa Moïse Diagne, Mamadou D. Barry, Fodé Y. Soumah, Annick Renevey, Georges Ki-Zerbo, Kékoura Ifono, Andrew Rambaut, Abdoul K. Soumah, Miles W. Carroll, Mamadou S. Bah, Joseph Akoi Bore, Ibrahima Camara, Mamadou S. Sow, Sébastien Calvignac-Spencer, Fodé A. Traore, Sophie Duraffour, Assaïtou Bah, John T. McCrone, Nathalie J. Vielle, Joshua Quick, Noël Tordo, Moussa Baldé, Mamadou Diop, Youssouf Sidibé, Martine Peeters, Madeleine Kourouma, Sakoba Keita, Mamadou B. Keita, Frédéric Le Marcis, Cé D. Saouromou, Anais Legand, Amadou Diallo, Pierre Formenty, Almudena Mari-Saez, Michael R. Wiley, Karifa Kourouma, Eric Delaporte, Barré Soropogui, Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Gamal Abdel Nasser de Conakry, Laboratoire des Fièvres Hémorragiques en Guinée, Bernhard Nocht Institute for Tropical Medicine - Bernhard-Nocht-Institut für Tropenmedizin [Hamburg, Germany] (BNITM), Institut Pasteur de Dakar, Réseau International des Instituts Pasteur (RIIP), Robert Koch Institute [Berlin] (RKI), German Center for Infection Research - Partner Site Hamburg-Lübeck-Borstel-Riems, German Centre for Infection Research (DZIF), Centre de Recherche et de Formation en Infectiologie de Guinée [Conakry, Guinée] (CERFIG), Triangle : action, discours, pensée politique et économique (TRIANGLE), École normale supérieure de Lyon (ENS de Lyon)-Université Lumière - Lyon 2 (UL2)-Sciences Po Lyon - Institut d'études politiques de Lyon (IEP Lyon), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), Hôpital National Donka, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, Epidemiology of Highly Pathogenic Microorganisms, Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), CEA Tech Grand-Est (DGDE), CEA Tech en régions (CEA-TECH-Reg), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut National de Santé Publique [Conakry, Guinée] (INSP), Ministère de la Santé [Conakry, Guinea], Laboratoire de Physique de l'Atmosphère et de l'Océan Siméon Fongang (LPAO-SF), École Supérieure Polytechnique de Dakar (ESP), Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD), Public Health England, University of Birmingham [Birmingham], Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), World Health Organization [Geneva], The University of Texas Medical Branch (UTMB), University of Nebraska Medical Center, University of Nebraska System, Institut Pasteur de Guinée, Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche Biomédicale des Armées [Antenne Marseille] (IRBA), University of Edinburgh, Division Prévention et Lutte contre la Maladie, Ministère de la Santé et de l’Hygiène Publique, Ecole Nationale Superieure de Lyon, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Infectious and Tropical Diseases Department [Montpellier], Institut de Recherche pour le Développement (IRD)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD), Max Planck Institute for Evolutionary Anthropology [Leipzig], Max-Planck-Gesellschaft, ANR-16-IDEX-0006,MUSE,MUSE(2016), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Centre National de la Recherche Scientifique (CNRS)-Sciences Po Lyon - Institut d'études politiques de Lyon (IEP Lyon), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Université Lumière - Lyon 2 (UL2)-École normale supérieure - Lyon (ENS Lyon), University of Oxford [Oxford], Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, INSB-INSB-Centre National de la Recherche Scientifique (CNRS), CEA Tech Alsace Champagne-Ardenne Lorraine, École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-Sciences Po Lyon - Institut d'études politiques de Lyon (IEP Lyon), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Michel de l'Hospital : laboratoire de recherche en sciences juridiques et politiques (CMH ), and Université Clermont Auvergne (UCA)

Subjects
Male, Zaire ebolavirus, Time Factors, viruses, Disease, Biology, medicine.disease_cause, Disease cluster, Models, Biological, Viral Zoonoses, Virus, Disease Outbreaks, 03 medical and health sciences, Ebola virus, 0302 clinical medicine, medicine, Animals, Humans, Survivors, 030212 general & internal medicine, Clade, Phylogeny, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Transmission (medicine), Guinea-2021, High-Throughput Nucleotide Sequencing, Outbreak, Hemorrhagic Fever, Ebola, [SHS.ANTHRO-SE]Humanities and Social Sciences/Social Anthropology and ethnology, Ebolavirus, Virology, 3. Good health, Democratic Republic of the Congo, Female, Persistent Infection, epidemiology, Guinea, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie
Abstract

Seven years after the declaration of the first epidemic of Ebola virus disease in Guinea, the country faced a new outbreak—between 14 February and 19 June 2021—near the epicentre of the previous epidemic1,2. Here we use next-generation sequencing to generate complete or near-complete genomes of Zaire ebolavirus from samples obtained from 12 different patients. These genomes form a well-supported phylogenetic cluster with genomes from the previous outbreak, which indicates that the new outbreak was not the result of a new spillover event from an animal reservoir. The 2021 lineage shows considerably lower divergence than would be expected during sustained human-to-human transmission, which suggests a persistent infection with reduced replication or a period of latency. The resurgence of Zaire ebolavirus from humans five years after the end of the previous outbreak of Ebola virus disease reinforces the need for long-term medical and social care for patients who survive the disease, to reduce the risk of re-emergence and to prevent further stigmatization. The viral lineage responsible for the February 2021 outbreak of Ebola virus disease in Guinea is nested within a clade that predominantly consists of genomes sampled during the 2013–2016 epidemic, suggesting that the virus might have re-emerged after a long period of latency within a previously infected individual.

Published
2021

48. SARS-CoV-2 targets neurons of 3D human brain organoids

Author

Henning Gruell, Heiner Schaal, Sandra Hauka, Pranty Abida‐Islam, Kai Wohlgemuth, Anand Ramani, Aruljothi Mariappan, Jörg Timm, Jay Gopalakrishnan, Elke Gabriel, Lisa Müller, Olivier Goureau, Carsten Korth, Dagmar Wieczorek, Alexander T. Dilthey, Torsten Houwaart, Ortwin Adams, Florian Klein, Heymut Omran, Philipp Niklas Ostermann, Marcel Andree, Andreas Müller-Schiffmann, Andreas Walker, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospital of Cologne [Cologne], University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), German Center for Infection Research, Partnersite Munich (DZIF), Center for Molecular Medicine [Cologne] (CMMC), and University of Cologne

Subjects
SARS‐CoV-2, Programmed cell death, Tau pathology, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), viruses, [SDV]Life Sciences [q-bio], Central nervous system, Hyperphosphorylation, neurons, tau Proteins, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Betacoronavirus, 03 medical and health sciences, 0302 clinical medicine, Chlorocebus aethiops, medicine, Organoid, Animals, Humans, Molecular Biology of Disease, skin and connective tissue diseases, Vero Cells, Molecular Biology, 030304 developmental biology, 0303 health sciences, General Immunology and Microbiology, brain organoids, SARS-CoV-2, General Neuroscience, fungi, Brain, Articles, Human brain, Microbiology, Virology & Host Pathogen Interaction, 3. Good health, respiratory tract diseases, Organoids, body regions, medicine.anatomical_structure, cell death, Soma, Nervous System Diseases, Neuroscience, 030217 neurology & neurosurgery
Abstract

COVID‐19 pandemic caused by SARS‐CoV‐2 infection is a public health emergency. COVID‐19 typically exhibits respiratory illness. Unexpectedly, emerging clinical reports indicate that neurological symptoms continue to rise, suggesting detrimental effects of SARS‐CoV‐2 on the central nervous system (CNS). Here, we show that a Düsseldorf isolate of SARS‐CoV‐2 enters 3D human brain organoids within 2 days of exposure. We identified that SARS‐CoV‐2 preferably targets neurons of brain organoids. Imaging neurons of organoids reveal that SARS‐CoV‐2 exposure is associated with altered distribution of Tau from axons to soma, hyperphosphorylation, and apparent neuronal death. Our studies, therefore, provide initial insights into the potential neurotoxic effect of SARS‐CoV‐2 and emphasize that brain organoids could model CNS pathologies of COVID‐19., In vitro exposure of cerebral organoids to coronavirus results in preferential infection and cell death of neuronal cells.

Published
2020

49. Rapid incorporation of Favipiravir by the fast and permissive viral RNA polymerase complex results in SARS-CoV-2 lethal mutagenesis

Author

Shannon, Ashleigh, Selisko, Barbara, Le, Nhung-Thi-Tuyet, Huchting, Johanna, Touret, Franck, Piorkowski, Géraldine, Fattorini, Véronique, Ferron, François, Decroly, Etienne, Meier, Chris, Coutard, Bruno, Peersen, Olve, Canard, Bruno, Architecture et fonction des macromolécules biologiques (AFMB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Hamburg, Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Colorado State University [Fort Collins] (CSU), This work was supported by the Fondation pour la Recherche Médicale (Aide aux équipes), the SCORE project H2020 SC1-PHE-Coronavirus-2020 (grant#101003627) to BCa, REACTing Covid-19 initiative (REsearch and ACTion targeting emerging infectious diseases) with the support of the Ministry of Solidarity and Health and the Ministry of Higher Eductation to BCa, ED and BCo, National Institutes of Health grant AI059130 to OP, and a grant from DZIF (German Center for Infection Research) to J.H. and C.M., European Commission GA 871029SCORE project H2020 SC1-PHE-Coronavirus-2020 101003627United States Department of Health & Human Services National Institutes of Health (NIH) - USA AI059130, ANR-20-COVI-0059,PROTEO-SARS-CoV-2,Protéomique du SARS-CoV-2(2020), and Ferron, François

Subjects
Models, Molecular, Science, viruses, Pneumonia, Viral, Viral Nonstructural Proteins, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Virus Replication, Antiviral Agents, Article, Betacoronavirus, Chlorocebus aethiops, Animals, lcsh:Science, Pandemics, Vero Cells, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Coronavirus RNA-Dependent RNA Polymerase, SARS-CoV-2, COVID-19, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Viral proteins, RNA-Dependent RNA Polymerase, Amides, COVID-19 Drug Treatment, Mutagenesis, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Pyrazines, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, RNA, Viral, lcsh:Q, Coronavirus Infections, Sequence Analysis
Abstract

The ongoing Corona Virus Disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has emphasized the urgent need for antiviral therapeutics. The viral RNA-dependent-RNA-polymerase (RdRp) is a promising target with polymerase inhibitors successfully used for the treatment of several viral diseases. We demonstrate here that Favipiravir predominantly exerts an antiviral effect through lethal mutagenesis. The SARS-CoV RdRp complex is at least 10-fold more active than any other viral RdRp known. It possesses both unusually high nucleotide incorporation rates and high-error rates allowing facile insertion of Favipiravir into viral RNA, provoking C-to-U and G-to-A transitions in the already low cytosine content SARS-CoV-2 genome. The coronavirus RdRp complex represents an Achilles heel for SARS-CoV, supporting nucleoside analogues as promising candidates for the treatment of COVID-19., Favipiravir (T-705) is an inhibitor of viral RNA-dependent-RNA-polymerases (RdRp) and clinical trials for the treatment of COVID-19 are ongoing. Here, the authors show that SARS-CoV nsp12 is the fastest known viral RdRp and they provide insights into the mechanism of action of Favipiravir, demonstrating that its antiviral effect on SARS-CoV-2 is primarily mediated through lethal mutagenesis.

Published
2020

50. Erratum for Wallenstein et al., 'ClbR Is the Key Transcriptional Activator of Colibactin Gene Expression in Escherichia coli'

Author

Jean-Philippe Nougayrède, Simone König, Rolf Müller, Nadège Bossuet-Greif, Nadine Rehm, Daniel Sauer, Marina Brinkmann, Alexander Wallenstein, Eric Oswald, Martina Selle, Jörg Overmann, Stefan Homburg, Boyke Bunk, Ulrich Dobrindt, Rudolf von Bünau, Cathrin Spröer, Haleluya Wami, Westfälische Wilhelms-Universität Münster = University of Münster (WWU), University of Würzburg, Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Helmholtz Centre for Infection Research (HZI), Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH / Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures (DSMZ), German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), Pharma Zentrale GmbH, Interdisciplinary Center for Clinical Research of the Medical Faculty Münster (Dob2/013/12), German Research Foundation (DO789/11-1)., German Research Foundation (SFB 479, TP A1)., Jean-Philippe, Nougayrede, and University of Münster

Subjects
Transcriptional Activation, Iron, VNTR, lcsh:QR1-502, secondary metabolite, medicine.disease_cause, Microbiology, lcsh:Microbiology, cytopathic effect, Host-Microbe Biology, 03 medical and health sciences, polyketide, Colibactin, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Gene expression, Escherichia coli, medicine, Molecular Biology, Transcriptional Activator, 030304 developmental biology, 0303 health sciences, 030306 microbiology, Chemistry, Escherichia coli Proteins, Gene Expression Regulation, Bacterial, Molecular biology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, QR1-502, Polyketides, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Erratum, RNA-seq, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Peptides, Research Article
Abstract

The nonribosomal peptide/polyketide hybrid colibactin can be considered a bacterial virulence factor involved in extraintestinal infection and also a procarcinogen. Nevertheless, and despite its genotoxic effect, colibactin expression can also inhibit bacterial or tumor growth and correlates with probiotic anti-inflammatory and analgesic properties. Although the biological function of this natural compound has been studied extensively, our understanding of the regulation of colibactin expression is still far from complete. We investigated in detail the role of regulatory elements involved in colibactin expression and in the growth conditions that promote colibactin expression. In this way, our data shed light on the regulatory mechanisms involved in colibactin expression and may support the expression and purification of this interesting nonribosomal peptide/polyketide hybrid for further molecular characterization., Colibactin is a nonribosomal peptide/polyketide hybrid natural product expressed by different members of the Enterobacteriaceae which can be correlated with induction of DNA double-strand breaks and interference with cell cycle progression in eukaryotes. Regulatory features of colibactin expression are only incompletely understood. We used Escherichia coli strain M1/5 as a model to investigate regulation of expression of the colibactin determinant at the transcriptional level and to characterize regulatory elements located within the colibactin pathogenicity island itself. We measured clbR transcription in vitro and observed that cultivation in defined minimal media led to increased colibactin expression relative to rich media. Transcription of clbR directly responds to iron availability. We also characterized structural DNA elements inside the colibactin determinant involved in ClbR-dependent regulation, i.e., ClbR binding sites and a variable number of tandem repeats located upstream of clbR. We investigated the impact of clbR overexpression or deletion at the transcriptome and proteome levels. Moreover, we compared global gene regulation under these conditions with that occurring upon overexpression or deletion of clbQ, which affects the flux of colibactin production. Combining the results of the transcriptome and proteome analyses with indirect measurements of colibactin levels by cell culture assays and an approximate quantification of colibactin via the second product of colibactin cleavage from precolibactin, N-myristoyl-d-asparagine, we demonstrate that the variable number of tandem repeats plays a significant regulatory role in colibactin expression. We identify ClbR as the only transcriptional activator known so far that is specific and essential for efficient regulation of colibactin production. IMPORTANCE The nonribosomal peptide/polyketide hybrid colibactin can be considered a bacterial virulence factor involved in extraintestinal infection and also a procarcinogen. Nevertheless, and despite its genotoxic effect, colibactin expression can also inhibit bacterial or tumor growth and correlates with probiotic anti-inflammatory and analgesic properties. Although the biological function of this natural compound has been studied extensively, our understanding of the regulation of colibactin expression is still far from complete. We investigated in detail the role of regulatory elements involved in colibactin expression and in the growth conditions that promote colibactin expression. In this way, our data shed light on the regulatory mechanisms involved in colibactin expression and may support the expression and purification of this interesting nonribosomal peptide/polyketide hybrid for further molecular characterization.

Published
2020

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