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1. Fatal Lassa fever in cynomolgus monkeys is associated with systemic viral dissemination and inflammation.

Author

Jimmy Hortion, Emeline Perthame, Blaise Lafoux, Laura Soyer, Stéphanie Reynard, Alexandra Journeaux, Clara Germain, Hélène Lopez-Maestre, Natalia Pietrosemoli, Nicolas Baillet, Séverine Croze, Catherine Rey, Catherine Legras-Lachuer, and Sylvain Baize

Subjects
Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract

The pathogenesis of Lassa fever has not yet been fully deciphered, particularly as concerns the mechanisms determining whether acute infection is controlled or leads to catastrophic illness and death. Using a cynomolgus monkey model of Lassa virus (LASV) infection reproducing the different outcomes of the disease, we performed histological and transcriptomic studies to investigate the dynamics of LASV infection and the immune mechanisms associated with survival or death. Lymphoid organs are an early major reservoir for replicating virus during Lassa fever, with LASV entering through the cortical sinus of draining lymph nodes regardless of disease outcome. However, subsequent viral tropism varies considerably with disease severity, with viral dissemination limited almost entirely to lymphoid organs and immune cells during nonfatal Lassa fever. By contrast, the systemic dissemination of LASV to all organs and diverse cell types, leading to infiltrations with macrophages and neutrophils and an excessive inflammatory response, is associated with a fatal outcome. These results provide new insight into early viral dynamics and the host response to LASV infection according to disease outcome.

Published
2024
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2. LBP2 Development and validation of a patient-centered autoevaluation questionnaire in systemic lupus erythematosus: LUPIN

Author

Zahir Amoura, Thierry Martin, Marianne Rivière, Xavier Mariette, Christophe Richez, Jacques-Eric Gottenberg, Laurent Perard, Denis Wahl, Jean Sibilia, Christian Agard, Marc André, Perrine Smets, François Chasset, Marc Scherlinger, Estibaliz Lazaro, Elisabeth Diot, Gilles Blaison, Baptiste Hervier, Isabelle Marie, Daniel Wendling, Jean-François Viallard, Arnaud Hot, Mathieu Puyade, Nicole Ferreira-Maldent, Amélie Servettaz, Ludovic Trefond, Roland Jaussaud, Christophe Deligny, Pauline Orquevaux, Pascal Roblot, Thomas Moulinet, Loïc Raffray, Frederic Renou, Jean François Kleinmann, Antonin Folliasson, Raphaëlle Rybak, Sabine Malivoir, Clara Baverez, Nicolas Baillet, Julien Campagne, Nicolas Girszyn, Cécile Fermont, Emmanuelle David, and Julie Lescanff

Subjects
Immunologic diseases. Allergy, RC581-607
Published
2024
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3. Pathogenesis of recent Lassa virus isolates from lineages II and VII in cynomolgus monkeys

Author

Mathieu Mateo, Jimmy Hortion, Emeline Perthame, Caroline Picard, Stéphanie Reynard, Alexandra Journeaux, Clara Germain, Xavier Carnec, Nicolas Baillet, Virginie Borges-Cardoso, Natalia Pietrosemoli, Audrey Vallve, Stéphane Barron, Ophélie Jourjon, Orianne Lacroix, Aurélie Duthey, Manon Dirheimer, Maïlys Daniau, Catherine Legras-Lachuer, Gregory Jouvion, Caroline Carbonnelle, Hervé Raoul, and Sylvain Baize

Subjects
Lassa virus, cynomolgus monkeys, pathogenesis, immune responses, viral hemorrhagic fevers, Infectious and parasitic diseases, RC109-216
Abstract

The area of Lassa virus (LASV) circulation is expanding, with the emergence of highly pathogenic new LASV lineages. Benin recently became an endemic country for LASV and has seen the emergence of a new LASV lineage (VII). The first two outbreaks in 2014 and 2016 showed a relatively high mortality rate compared to other outbreaks. We infected cynomolgus monkeys with two strains belonging to lineage II and lineage VII that were isolated from deceased patients during the 2016 outbreak in Benin. The lineage VII strain (L7) caused uniform mortality. Death was associated with uncontrolled viral replication, unbalanced inflammatory responses characterized by increased concentrations of pro- and anti-inflammatory mediators, and the absence of efficient immune responses, resembling the pathogenesis associated with the prototypic Josiah strain in monkeys. The lineage II strain (L2) showed apparently lower virulence than its counterpart, with a prolonged time to death and a lower mortality rate. Prolonged survival was associated with better control of viral replication, a moderate inflammatory response, and efficient T-cell responses. Transcriptomic analyses also highlighted important differences in the immune responses associated with the outcome. Both strains caused strong inflammation in several organs. Notably, meningitis and encephalitis were observed in the cerebral cortex and cerebellum in all monkeys, independently of the outcome. Due to their apparently high pathogenicity, emerging strains from lineage VII should be considered in preclinical vaccine testing. Lineage II would also be beneficial in pathogenesis studies to study the entire spectrum of Lassa fever severity.

Published
2022
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4. Systemic viral spreading and defective host responses are associated with fatal Lassa fever in macaques

Author

Nicolas Baillet, Stéphanie Reynard, Emeline Perthame, Jimmy Hortion, Alexandra Journeaux, Mathieu Mateo, Xavier Carnec, Justine Schaeffer, Caroline Picard, Laura Barrot, Stéphane Barron, Audrey Vallve, Aurélie Duthey, Frédéric Jacquot, Cathy Boehringer, Grégory Jouvion, Natalia Pietrosemoli, Rachel Legendre, Marie-Agnès Dillies, Richard Allan, Catherine Legras-Lachuer, Caroline Carbonnelle, Hervé Raoul, and Sylvain Baize

Subjects
Biology (General), QH301-705.5
Abstract

Baillet et al. use the cynomolgus monkey model to model Lassa virus and associated Lassa fever (LF). They provide a full characterisation of LF pathogenesis with the aim of assisting the development of early diagnostic tools.

Published
2021
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5. Early control of viral load by favipiravir promotes survival to Ebola virus challenge and prevents cytokine storm in non-human primates.

Author

Stéphanie Reynard, Emilie Gloaguen, Nicolas Baillet, Vincent Madelain, Jérémie Guedj, Hervé Raoul, Xavier de Lamballerie, Jimmy Mullaert, and Sylvain Baize

Subjects
Arctic medicine. Tropical medicine, RC955-962, Public aspects of medicine, RA1-1270
Abstract

Ebola virus has been responsible for two major epidemics over the last several years and there has been a strong effort to find potential treatments that can improve the disease outcome. Antiviral favipiravir was thus tested on non-human primates infected with Ebola virus. Half of the treated animals survived the Ebola virus challenge, whereas the infection was fully lethal for the untreated ones. Moreover, the treated animals that did not survive died later than the controls. We evaluated the hematological, virological, biochemical, and immunological parameters of the animals and performed proteomic analysis at various timepoints of the disease. The viral load strongly correlated with dysregulation of the biological functions involved in pathogenesis, notably the inflammatory response, hemostatic functions, and response to stress. Thus, the management of viral replication in Ebola virus disease is of crucial importance in preventing the immunopathogenic disorders and septic-like shock syndrome generally observed in Ebola virus-infected patients.

Published
2021
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6. E3 Ligase ITCH Interacts with the Z Matrix Protein of Lassa and Mopeia Viruses and Is Required for the Release of Infectious Particles

Author

Nicolas Baillet, Sophie Krieger, Xavier Carnec, Mathieu Mateo, Alexandra Journeaux, Othmann Merabet, Valérie Caro, Frédéric Tangy, Pierre-Olivier Vidalain, and Sylvain Baize

Subjects
lassa fever, lasv, mopv, itch, z matrix protein, yeast two-hybrid screening, egress, infection, Microbiology, QR1-502
Abstract

Lassa virus (LASV) and Mopeia virus (MOPV) are two closely related, rodent-born mammarenaviruses. LASV is the causative agent of Lassa fever, a deadly hemorrhagic fever endemic in West Africa, whereas MOPV is non-pathogenic in humans. The Z matrix protein of arenaviruses is essential to virus assembly and budding by recruiting host factors, a mechanism that remains partially defined. To better characterize the interactions involved, a yeast two-hybrid screen was conducted using the Z proteins from LASV and MOPV as a bait. The cellular proteins ITCH and WWP1, two members of the Nedd4 family of HECT E3 ubiquitin ligases, were found to bind the Z proteins of LASV, MOPV and other arenaviruses. The PPxY late-domain motif of the Z proteins is required for the interaction with ITCH, although the E3 ubiquitin-ligase activity of ITCH is not involved in Z ubiquitination. The silencing of ITCH was shown to affect the replication of the old-world mammarenaviruses LASV, MOPV, Lymphocytic choriomeningitis virus (LCMV) and to a lesser extent Lujo virus (LUJV). More precisely, ITCH was involved in the egress of virus-like particles and the release of infectious progeny viruses. Thus, ITCH constitutes a novel interactor of LASV and MOPV Z proteins that is involved in virus assembly and release.

Published
2019
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7. Autophagy Promotes Infectious Particle Production of Mopeia and Lassa Viruses

Author

Nicolas Baillet, Sophie Krieger, Alexandra Journeaux, Valérie Caro, Frédéric Tangy, Pierre-Olivier Vidalain, and Sylvain Baize

Subjects
LASV, MOPV, Z matrix protein, NDP52, TAX1BP1, autophagy, replication, yeast two-hybrid screening, Microbiology, QR1-502
Abstract

Lassa virus (LASV) and Mopeia virus (MOPV) are two closely related Old-World mammarenaviruses. LASV causes severe hemorrhagic fever with high mortality in humans, whereas no case of MOPV infection has been reported. Comparing MOPV and LASV is a powerful strategy to unravel pathogenic mechanisms that occur during the course of pathogenic arenavirus infection. We used a yeast two-hybrid approach to identify cell partners of MOPV and LASV Z matrix protein in which two autophagy adaptors were identified, NDP52 and TAX1BP1. Autophagy has emerged as an important cellular defense mechanism against viral infections but its role during arenavirus infection has not been shown. Here, we demonstrate that autophagy is transiently induced by MOPV, but not LASV, in infected cells two days after infection. Impairment of the early steps of autophagy significantly decreased the production of MOPV and LASV infectious particles, whereas a blockade of the degradative steps impaired only MOPV infectious particle production. Our study provides insights into the role played by autophagy during MOPV and LASV infection and suggests that this process could partially explain their different pathogenicity.

Published
2019
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8. A single-shot Lassa vaccine induces long-term immunity and protects cynomolgus monkeys against heterologous strains

Author

P. Moreau, Ophélie Jourjon, Virginie Borges-Cardoso, Caroline Picard, Manon Dirheimer, Xavier Carnec, Lyne Fellmann, Othmann Merabet, Clara Germain, Mathieu Mateo, Aurélie Duthey, Stéphanie Reynard, Alexandra Journeaux, Hervé Raoul, Jimmy Hortion, Frédéric Tangy, Gregory Jouvion, Audrey Vallve, Stéphane Barron, Caroline Carbonnelle, Nicolas Baillet, Orianne Lacroix, Sylvain Baize, Biologie des Infections Virales Émergentes - Biology of Emerging Viral Infections (UBIVE), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP), Laboratoire P4 - Jean Mérieux, Centre Européen de Virologie/Immunologie-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), École nationale vétérinaire - Alfort (ENVA), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Université de Strasbourg (UNISTRA), Génomique Virale et Vaccination, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This study was entirely funded by a grant from the Coalition for Epidemic Preparedness and Innovations (CEPI-CfP-001) to S. Baize, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), 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)-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)-Institut Pasteur [Paris], École nationale vétérinaire d'Alfort (ENVA), Baize, Sylvain, and 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 Pasteur [Paris] (IP)

Subjects
0301 basic medicine, viruses, Heterologous, medicine.disease_cause, Measles virus, 03 medical and health sciences, [SDV.IMM.VAC] Life Sciences [q-bio]/Immunology/Vaccinology, Lassa Fever, 0302 clinical medicine, Immune system, medicine, Animals, 030212 general & internal medicine, Vector (molecular biology), Lassa virus, biology, virus diseases, Outbreak, Viral Vaccines, General Medicine, Vaccine efficacy, biology.organism_classification, Virology, 3. Good health, Nucleoprotein, Africa, Western, Macaca fascicularis, Nucleoproteins, 030104 developmental biology, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology
Abstract

Acknowledgments: We thank P. Regnard (Silabe, Strasbourg) for medical care given to the monkeys. We thank S. Mundweiller, S. Godard, E. Moissonnier, D. Thomas, S. Mély, B. Labrosse, D. Pannetier, and C. Léculier (P4 INSERM–Jean Mérieux, US003, INSERM) for assistance in conducting the BSL-4 experiments. We are grateful to G. Fourcaud and B. Lafoux (Institut Pasteur, CIRI, Lyon) for technical help with histological studies. We thank S. Becker for providing us with the Josiah strain and T. G. Ksiasek, P. E. Rollin, and P. Jahrling for the LASV monoclonal antibodies. We also thank L. Branco (Zalgen Labs) for providing recombinant proteins. We are grateful to THEMIS Bioscience GmbH, a wholly owned subsidiary of Merck & Co. Inc. (E. Tauber, A. Kort, K. Ramsauer, S. Schrauf, Y. Tomberger, and R. Tschismarov), to the Coalition for Epidemic Preparedness and Innovations (R. Hatchett, G. Thiry, and M. Saville), and to C. Gerke (Department of Innovation Development, Institut Pasteur) for invaluable support; International audience; A safe and protective Lassa virus vaccine is crucially needed in Western Africa to stem the recurrent outbreaks of Lassa virus infections in Nigeria and the emergence of Lassa virus in previously unaffected countries, such as Benin and Togo. Major challenges in developing a Lassa virus vaccine include the high diversity of circulating strains and their reemergence from 1 year to another. To address each of these challenges, we immunized cynomolgus monkeys with a measles virus vector expressing the Lassa virus glycoprotein and nucleoprotein of the prototypic Lassa virus strain Josiah (MeV-NP). To evaluate vaccine efficacy against heterologous strains of Lassa virus, we challenged the monkeys a month later with heterologous strains from lineage II or lineage VII, finding that the vaccine was protective against these strains. A second cohort of monkeys was challenged 1 year later with the homologous Josiah strain, finding that a single dose of MeV-NP was sufficient to protect all vaccinated monkeys. These studies demonstrate that MeV-NP can generate both long-lasting immune responses and responses that are able to protect against diverse strains of Lassa virus.

Published
2021
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9. Early control of viral load by favipiravir promotes survival to Ebola virus challenge and prevents cytokine storm in non-human primates

Author

Hervé Raoul, Nicolas Baillet, Xavier de Lamballerie, Emilie Gloaguen, Jeremie Guedj, Stéphanie Reynard, Sylvain Baize, Jimmy Mullaert, Vincent Madelain, Biologie des Infections Virales Émergentes - Biology of Emerging Viral Infections (UBIVE), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Laboratoire P4 - Jean Mérieux, Centre Européen de Virologie/Immunologie-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 Pasteur [Paris]-Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre International de Recherche en Infectiologie - UMR (CIRI), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]

Subjects
0301 basic medicine, RNA viruses, Viral Diseases, Physiology, T-Lymphocytes, viruses, RC955-962, Cancer Treatment, Disease, medicine.disease_cause, Virus Replication, Pathology and Laboratory Medicine, White Blood Cells, 0302 clinical medicine, Medical Conditions, Animal Cells, Arctic medicine. Tropical medicine, Immune Physiology, Medicine and Health Sciences, Medicine, 030212 general & internal medicine, Hemostatic function, Immune Response, Innate Immune System, T Cells, virus diseases, Viral Load, Ebolavirus, 3. Good health, Body Fluids, Infectious Diseases, Blood, Oncology, Medical Microbiology, Pyrazines, Filoviruses, Viral Pathogens, Viruses, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Cytokines, Public aspects of medicine, RA1-1270, Pathogens, Anatomy, Cellular Types, Cytokine Release Syndrome, Ebola Virus, Viral load, Research Article, Immune Cells, Immunology, Viremia, Cytokine Therapy, Favipiravir, Antiviral Agents, Microbiology, Blood Plasma, 03 medical and health sciences, Signs and Symptoms, Virology, Animals, Microbial Pathogens, Inflammation, Ebola virus, Blood Cells, business.industry, Hemorrhagic Fever Viruses, Public Health, Environmental and Occupational Health, Organisms, Biology and Life Sciences, Cell Biology, Hemorrhagic Fever, Ebola, Molecular Development, medicine.disease, Amides, Disease Models, Animal, Macaca fascicularis, 030104 developmental biology, Viral replication, Immune System, Clinical Medicine, business, Cytokine storm, Viral Transmission and Infection, Developmental Biology
Abstract

Ebola virus has been responsible for two major epidemics over the last several years and there has been a strong effort to find potential treatments that can improve the disease outcome. Antiviral favipiravir was thus tested on non-human primates infected with Ebola virus. Half of the treated animals survived the Ebola virus challenge, whereas the infection was fully lethal for the untreated ones. Moreover, the treated animals that did not survive died later than the controls. We evaluated the hematological, virological, biochemical, and immunological parameters of the animals and performed proteomic analysis at various timepoints of the disease. The viral load strongly correlated with dysregulation of the biological functions involved in pathogenesis, notably the inflammatory response, hemostatic functions, and response to stress. Thus, the management of viral replication in Ebola virus disease is of crucial importance in preventing the immunopathogenic disorders and septic-like shock syndrome generally observed in Ebola virus-infected patients., Author summary Ebola virus was responsible for several epidemics in the recent years and is now considered as a major public health concern in Central and West African countries. We and others demonstrated that pathogenic events observed during Ebola virus disease are linked to a deleterious immune response. However, the mechanisms implicated are not fully understood. Here, we studied immune responses depending on the viral loads observed in infected cynomolgus monkeys. An antiviral treatment allowed the reduction of viral load in some animals and we observed that these animals did not experience deleterious immune response and the loss of hemostasis. The release of pathogen-associated molecular patterns may thus be limited by the inhibition of viral replication, avoiding the overstimulation of the immune system and consequently the pathogenic events observed in Ebola virus disease.

Published
2021
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10. E3 Ligase ITCH Interacts with the Z Matrix Protein of Lassa and Mopeia Viruses and Is Required for the Release of Infectious Particles

Author

Alexandra Journeaux, Sophie Krieger, Nicolas Baillet, Sylvain Baize, Pierre-Olivier Vidalain, Othmann Merabet, Valérie Caro, Xavier Carnec, Mathieu Mateo, Frédéric Tangy, Biologie des Infections Virales Émergentes - Biology of Emerging Viral Infections (UBIVE), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP), Environnement et Risques infectieux - Environment and Infectious Risks (ERI), Institut Pasteur [Paris] (IP), Génomique virale et vaccination, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This research was funded by the Fondation pour l’Innovation en Infectiologie (FINOVI) (Lyon, France),the Fondation pour la Recherche Médicale (FRM) (France), and by an internal grant at the Institut Pasteur (PTR414). N.B. held a fellowship from the Délégation Générale de l’Armement (French Army)., Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut Pasteur [Paris], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), MATEO, MATHIEU, and 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 Pasteur [Paris] (IP)

Subjects
0301 basic medicine, viruses, lcsh:QR1-502, MOPV, NEDD4, medicine.disease_cause, lcsh:Microbiology, LASV, Chlorocebus aethiops, Lassa fever, Arenaviridae, Lujo virus, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology, ITCH, 3. Good health, Ubiquitin ligase, egress, Infectious Diseases, yeast two-hybrid screening, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Ubiquitin-Protein Ligases, 030106 microbiology, Lymphocytic choriomeningitis, Virus, Article, 03 medical and health sciences, Viral Proteins, Virology, Two-Hybrid System Techniques, medicine, Z matrix protein, Gene silencing, Animals, Humans, Lassa virus, Vero Cells, Host Microbial Interactions, Virus Assembly, medicine.disease, biology.organism_classification, infection, Repressor Proteins, 030104 developmental biology, HEK293 Cells, biology.protein, HeLa Cells
Abstract

International audience; Lassa virus (LASV) and Mopeia virus (MOPV) are two closely related, rodent-born mammarenaviruses. LASV is the causative agent of Lassa fever, a deadly hemorrhagic fever endemic in West Africa, whereas MOPV is non-pathogenic in humans. The Z matrix protein of arenaviruses is essential to virus assembly and budding by recruiting host factors, a mechanism that remains partially defined. To better characterize the interactions involved, a yeast two-hybrid screen was conducted using the Z proteins from LASV and MOPV as a bait. The cellular proteins ITCH and WWP1, two members of the Nedd4 family of HECT E3 ubiquitin ligases, were found to bind the Z proteins of LASV, MOPV and other arenaviruses. The PPxY late-domain motif of the Z proteins is required for the interaction with ITCH, although the E3 ubiquitin-ligase activity of ITCH is not involved in Z ubiquitination. The silencing of ITCH was shown to affect the replication of the old-world mammarenaviruses LASV, MOPV, Lymphocytic choriomeningitis virus (LCMV) and to a lesser extent Lujo virus (LUJV). More precisely, ITCH was involved in the egress of virus-like particles and the release of infectious progeny viruses. Thus, ITCH constitutes a novel interactor of LASV and MOPV Z proteins that is involved in virus assembly and release.

Published
2020
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11. Vaccines inducing immunity to Lassa virus glycoprotein and nucleoprotein protect macaques after a single shot

Author

Audrey Vallve, Laura Barrot, Caroline Picard, Nicolas Baillet, Sylvain Baize, Hervé Raoul, Mathieu Mateo, Frédéric Tangy, Emeline Perthame, Alexandra Journeaux, Stéphanie Reynard, Natalia Pietrosemoli, Jean Armengaud, Lyne Fellmann, Xavier Carnec, Richard Allan, Caroline Carbonnelle, Stéphane Barron, Catherine Legras-Lachuer, Kenzo-Hugo Hillion, Jean-Charles Gaillard, Marie-Agnès Dillies, Justine Schaeffer, Biologie des Infections Virales Émergentes - Biology of Emerging Viral Infections (UBIVE), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP), Viroscan3D SAS [Lyon, France], Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Laboratoire P4 Jean Mérieux-Inserm [Lyon] (Unité de service 3), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Européen de Recherche en Virologie et Immunologie [Lyon] (Tour Inserm CERVI), Université de Strasbourg (UNISTRA), Laboratoire Innovations technologiques pour la Détection et le Diagnostic (LI2D), 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), Génomique virale et vaccination, This study was supported by the Grand Programme Fédérateur–Vaccinologie of the Institut Pasteur and the Fondation pour la Recherche Médicale (FRM team grant 2013). The MOPEVAC vaccine was supported by the LABEX ECOFECT (ANR-11-LABX-0048, Lyon University), within the program 'Investissements d’Avenir' (ANR-11-IDEX-0007, French National Research Agency). The MeV-based LASV vaccines received funds from the Fondation pour l’Innovation en Infectiologie (FINOVI). M.M. was supported by a Pasteur Roux fellowship., ANR-11-LABX-0048,ECOFECT,Dynamiques eco-évolutives des maladies infectieuses(2011), Centre International de Recherche en Infectiologie - UMR (CIRI), 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)-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)-Institut Pasteur [Paris], and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Male, Proteomics, 030106 microbiology, Biology, medicine.disease_cause, Measles, Cell Line, Measles virus, 03 medical and health sciences, Viral Proteins, Immune system, Lassa Fever, Immunity, medicine, Animals, Humans, Lassa fever, Lassa virus, Glycoproteins, Vaccination, General Medicine, medicine.disease, biology.organism_classification, Flow Cytometry, Virology, 3. Good health, Nucleoprotein, Macaca fascicularis, 030104 developmental biology, Nucleoproteins, Immunization, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, Transcriptome
Abstract

International audience; Lassa fever is a major threat in Western Africa. The large number of people living at risk for this disease calls for the development of a vaccine against Lassa virus (LASV). We generated live-attenuated LASV vaccines based on measles virus and Mopeia virus platforms and expressing different LASV antigens, with the aim to develop a vaccine able to protect after a single shot. We compared the efficacy of these vaccines against LASV in cynomolgus monkeys. The vaccines were well tolerated and protected the animals from LASV infection and disease after a single immunization but with varying efficacy. Analysis of the immune responses showed that complete protection was associated with robust secondary T cell and antibody responses against LASV. Transcriptomic and proteomic analyses showed an early activation of innate immunity and T cell priming after immunization with the most effective vaccines, with changes detectable as early as 2 days after immunization. The most efficacious vaccine candidate, a measles vector simultaneously expressing LASV glycoprotein and nucleoprotein, has been selected for further clinical evaluation.

Published
2019
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12. Immune parameters and outcomes during Ebola virus disease

Author

Hervé Raoul, Emilie Gloaguen, Cédric Laouénan, Justine Schaeffer, Alexandra Journeaux, Sylvain Baize, Stéphanie Reynard, Natalia Pietrosemoli, Jimmy Mullaert, Mathieu Mateo, Hugo Varet, Nicolas Baillet, Biologie des Infections Virales Émergentes - Biology of Emerging Viral Infections (UBIVE), Centre International de Recherche en Infectiologie - UMR (CIRI), 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)-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)-Institut Pasteur [Paris], Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Département d'épidémiologie, biostatistique et recherche clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire P4 - Jean Mérieux, Centre Européen de Virologie/Immunologie-Institut National de la Santé et de la Recherche Médicale (INSERM), French Ministry of Foreign Affairs, the Agence Française de Développement, and the Institut Pasteur., École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Varet, Hugo, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), 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)-Institut Pasteur [Paris] (IP)

Subjects
0301 basic medicine, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], viruses, Disease, medicine.disease_cause, Virus, 03 medical and health sciences, 0302 clinical medicine, Immune system, Virology, Medicine, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Innate immunity, Infectious disease, Innate immune system, Ebola virus, business.industry, Septic shock, Outbreak, General Medicine, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Infectious disease (medical specialty), 030220 oncology & carcinogenesis, Immunology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Chemokines, Clinical Medicine, business
Abstract

Background The West African Ebola virus epidemic from 2014-2016 highlighted the lack of knowledge about the pathogenicity of the virus and the factors responsible for outcome. A performant and rapid diagnosis is of crucial importance, as is overcoming the difficulty of providing high-quality patient management during such an extensive outbreak. Here, we propose to study the role of the immune mediators during Ebola virus disease and to define some molecules of importance in the outcome. Methods Plasma from Guinean patients sampled during the outbreak were analyzed using RT-qPCR, magnetic bead assay, ELISA, and high-quality statistical analyses. We also performed a transcriptomic analysis in leukocytes samples. Therefore, we deeply characterized the immune responses involved in Ebola virus disease. Results We evaluated the immune patterns depending on the outcome of the disease. Survivors presented an efficient and well-balanced immune response, whereas fatalities were characterized by an intense inflammatory response, overexpression of multiple cytokines, and a "chemokine storm." The plasma concentration of most of the parameters tested increased until death. Statistical analyses also allowed us to define a panel of markers highly predictive of outcome. Conclusion The immune response observed in fatalities was highly similar to that characterizing septic shock syndrome. Our results suggest that immune responses can play a major pathogenic role during severe Ebola virus infection and argue in favor of therapeutic approaches that act on both viral replication and the induction of shock syndrome. Funding French Ministry of Foreign Affairs, the Agence Francaise de Developpement, and the Institut Pasteur.

Published
2018
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13. One-shot immunization using a Measles/Lassa vaccine fully protects cynomolgus monkeys against Lassa fever

Author

M. Jourdain, Alexandra Fizet, Stéphanie Reynard, Audrey Vallve, Laura Barrot, Hervé Raoul, Nicolas Baillet, Caroline Carbonnelle, Stéphane Barron, Caroline Picard, Mathieu Mateo, Xavier Carnec, F. Tangy, Justine Schaeffer, and Sylvain Baize

Subjects
Microbiology (medical), One shot, Infectious Diseases, Immunization, business.industry, Medicine, General Medicine, business, Lassa fever, medicine.disease, Measles, Virology
Published
2019
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