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1. Host Cell Restriction Factors of Bunyaviruses and Viral Countermeasures

Author

Solène Lerolle, Natalia Freitas, François-Loïc Cosset, Vincent Legros, Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), 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), 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), and ANR-16-IDEX-0005,IDEXLYON,IDEXLYON(2016)

Subjects
Bunyaviridae, [SDV]Life Sciences [q-bio], Virion, Review, Genome, Viral, Genomics, interferon, Bunyaviridae Infections, Virus Replication, Microbiology, bunyaviruses, restriction factors, QR1-502, Immunity, Innate, Receptors, Pattern Recognition, Host-Pathogen Interactions, Interferon Type I, Immune Tolerance, Animals, Humans, viral countermeasures, innate immunity, Biomarkers
Abstract

International audience; The Bunyavirales order comprises more than 500 viruses (generally defined as bunyaviruses) classified into 12 families. Some of these are highly pathogenic viruses infecting different hosts, including humans, mammals, reptiles, arthropods, birds, and/or plants. Host cell sensing of infection activates the innate immune system that aims at inhibiting viral replication and propagation. Upon recognition of pathogen-associated molecular patterns (PAMPs) by cellular pattern recognition receptors (PRRs), numerous signaling cascades are activated, leading to the production of interferons (IFNs). IFNs act in an autocrine and paracrine manner to establish an antiviral state by inducing the expression of hundreds of IFN-stimulated genes (ISGs). Some of these ISGs are known to restrict bunyavirus infection. Along with other constitutively expressed host cellular factors with antiviral activity, these proteins (hereafter referred to as “restriction factors”) target different steps of the viral cycle, including viral entry, genome transcription and replication, and virion egress. In reaction to this, bunyaviruses have developed strategies to circumvent this antiviral response, by avoiding cellular recognition of PAMPs, inhibiting IFN production or interfering with the IFN-mediated response. Herein, we review the current knowledge on host cellular factors that were shown to restrict infections by bunyaviruses. Moreover, we focus on the strategies developed by bunyaviruses in order to escape the antiviral state developed by the infected cells.

Published
2021
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2. Impact of the SARS-COV-2 outbreak on epidemiology and management of major traumain France: a registry-based study (the COVITRAUMA study)

Author

Jean-Denis Moyer, Arthur James, Clément Gakuba, Mathieu Boutonnet, Emeline Angles, Emmanuel Rozenberg, Jean Bardon, Thomas Clavier, Vincent Legros, Marie Werner, Quentin Mathais, Véronique Ramonda, Pierre Le Minh, Yann Berthelot, Clélia Colas, Julien Pottecher, Tobias Gauss, and the Traumabase Group, Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), Université de Paris (UP), Hôpital Beaujon, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Anesthésie réanimation [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Soins Intensifs [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital d'instruction des Armées Percy, Service de Santé des Armées, Service Anesthésie - Réanimation [Bordeaux], CHU Bordeaux [Bordeaux], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service d'anesthésie-réanimation SAMU94-SMUR94 [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service Anesthésie et soins intensifs [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Centre Hospitalier Universitaire de Reims (CHU Reims), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), 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), Center for Immunology of Viral Infections and Autoimmune Diseases, Le Kremlin Bicêtre, Hopital d'instruction des armées Sainte-Anne [Toulon] (HIA), CHU de Toulouse, Pole d'anesthésie Réanimation, Hôpital Paule de Viguier, Toulouse F-31059, France, CHU Toulouse [Toulouse], Capgemini [Paris], Capgemini, Department of Anesthesiology, Intensive care and Perioperative medicine - Hautepierre Hospital, Strasbourg, UFR Médecine [Santé] - Université Paris Cité (UFR Médecine UPCité), Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Pôle Anesthésie Réanimation [CHU de Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Pôle d'anesthésie Réanimation [CHU de Toulouse], and Gestionnaire, HAL Sorbonne Université 5

Subjects
Adult, Male, medicine.medical_specialty, Critical Care and Intensive Care Medicine, Trauma, 03 medical and health sciences, 0302 clinical medicine, Trauma Centers, Health care, Pandemic, Epidemiology, Humans, Medicine, Registries, 030212 general & internal medicine, Traumacenter, Disease management (health), Pandemics, Original Research, Retrospective Studies, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, SARS-CoV-2, business.industry, Major trauma, lcsh:Medical emergencies. Critical care. Intensive care. First aid, Disease Management, Outbreak, COVID-19, 030208 emergency & critical care medicine, Retrospective cohort study, lcsh:RC86-88.9, medicine.disease, 3. Good health, Hospitalization, Communicable Disease Control, Emergency medicine, Cohort, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Emergency Medicine, Female, France, business, Delivery of Health Care
Abstract

Background Emerging evidence suggests that the reallocation of health care resources during the COVID-19 pandemic negatively impacts health care system. This study describes the epidemiology and the outcome of major trauma patients admitted to centers in France during the first wave of the COVID-19 outbreak. Methods This retrospective observational study included all consecutive trauma patients aged 15 years and older admitted into 15 centers contributing to the TraumaBase® registry during the first wave of the SARS-CoV-2 pandemic in France. This COVID-19 trauma cohort was compared to historical cohorts (2017–2019). Results Over a 4 years-study period, 5762 patients were admitted between the first week of February and mid-June. This cohort was split between patients admitted during the first 2020 pandemic wave in France (pandemic period, 1314 patients) and those admitted during the corresponding period in the three previous years (2017–2019, 4448 patients). Trauma patient demographics changed substantially during the pandemic especially during the lockdown period, with an observed reduction in both the absolute numbers and proportion exposed to road traffic accidents and subsequently admitted to traumacenters (348 annually 2017–2019 [55.4% of trauma admissions] vs 143 [36.8%] in 2020 p Conclusions During this first wave of COVID-19 in France, and more specifically during lockdown there was a significant reduction of patients admitted to designated trauma centers. Despite the reallocation and reorganization of medical resources this reduction prevented the saturation of the trauma rescue chain and has allowed maintaining a high quality of care for trauma patients.

Published
2021
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3. Total gastrectomy for severe proton pump inhibitor-induced hypomagnesemia in a MEN1/Zollinger Ellison syndrome patient

Author

Sophie Deguelte, Vincent Legros, Guillaume Cadiot, Brigitte Delemer, Marine Perrier, Hedia Brixi, R. Kianmanesh, Centre de Recherche en Sciences et Technologies de l'Information et de la Communication - EA 3804 (CRESTIC), and Université de Reims Champagne-Ardenne (URCA)

Subjects
Male, Peptic Ulcer, endocrine system, medicine.medical_specialty, medicine.drug_class, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Peptic, Proton-pump inhibitor, Gastroenterology, Hypomagnesemia, Zollinger-Ellison Syndrome, 03 medical and health sciences, 0302 clinical medicine, Gastrectomy, Internal medicine, Multiple Endocrine Neoplasia Type 1, medicine, Humans, Multiple endocrine neoplasia, ComputingMilieux_MISCELLANEOUS, Gastrinoma, Frailty, Hepatology, business.industry, Stomach, Proton Pump Inhibitors, Middle Aged, medicine.disease, digestive system diseases, Zollinger-Ellison syndrome, 3. Good health, Treatment Outcome, 030220 oncology & carcinogenesis, Gastric acid, 030211 gastroenterology & hepatology, business, Magnesium Deficiency, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

We report here the first case of life-threatening hypomagnesemia in a Zollinger-Ellison syndrome patient with multiple endocrine neoplasia type 1 (MEN1) syndrome. The severe symptomatic hypomagnesemia proved to be due to proton pump inhibitors (PPIs), but withdrawal of PPIs led to early severe peptic complications despite a substitution by histamine H2-receptor antagonist therapy. Simultaneous management of life-threatening hypomagnesemia, severe gastric acid hypersecretion and MEN1-associated gastrinomas was complex. A total gastrectomy was performed in order to definitely preclude the use of PPIs in this frail patient who was not eligible for curative pancreatoduodenal resection.

Published
2021
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4. The SARS-CoV-2 Envelope and Membrane proteins modulate maturation and retention of the Spike protein, allowing optimal formation of VLPs in presence of Nucleoprotein

Author

Bertrand Boson, Bingjie Zhou, Vincent Legros, Dimitri Lavillette, Cyrille Mathieu, François-Loïc Cosset, Solène Denolly, Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), 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), Immunobiologie des infections virales – Immunobiology of Viral Infections (IbIV), 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)

Subjects
0303 health sciences, Chemistry, viruses, 030302 biochemistry & molecular biology, Mutant, Cell, Golgi apparatus, 3. Good health, Nucleoprotein, Cell biology, 03 medical and health sciences, symbols.namesake, medicine.anatomical_structure, Membrane protein, Cytoplasm, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, symbols, medicine, Secretory pathway, Intracellular, 030304 developmental biology
Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a β-coronavirus, is the causative agent of the COVID-19 pandemic. Like for other coronaviruses, its particles are composed of four structural proteins, namely Spike S, Envelope E, Membrane M and Nucleoprotein N proteins. The involvement of each of these proteins and their interplays during the assembly process of this new virus are poorly-defined and are likely β-coronavirus-type different. Therefore, we sought to investigate how SARS-CoV-2 behaves for its assembly by expression assays of S, in combination with E, M and/or N. By combining biochemical and imaging assays, we showed that E and M regulate intracellular trafficking of S and hence its furin-mediated processing. Indeed, our imaging data revealed that S remains at ERGIC or Golgi compartments upon expression of E or M, like for SARS-CoV-2 infected cells. By studying a mutant of S, we showed that its cytoplasmic tail, and more specifically, its C-terminal retrieval motif, is required for the M-mediated retention in the ERGIC, whereas E induces S retention by modulating the cell secretory pathway. We also highlighted that E and M induce a specific maturation of S N-glycosylation, which is observed on particles and lysates from infected cells independently of its mechanisms of intracellular retention. Finally, we showed that both M, E and N are required for optimal production of virus-like-proteins. Altogether, our results indicated that E and M proteins influence the properties of S proteins to promote assembly of viral particles. Our results therefore highlight both similarities and dissimilarities in these events, as compared to other β-coronaviruses.Author SummaryThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the COVID-19 pandemic. Its viral particles are composed of four structural proteins, namely Spike S, Envelope E, Membrane M and Nucleoprotein N proteins, though their involvement in the virion assembly remain unknown for this particular coronavirus. Here we showed that presence of E and M influence the localization and maturation of S protein, in term of cleavage and N-glycosylation maturation. Indeed, E protein is able to slow down the cell secretory pathway whereas M-induced retention of S requires the retrieval motif in S C-terminus. We also highlighted that E and M might regulate the N glycosylation maturation of S independently of its intracellular retention mechanism. Finally, we showed that the four structural proteins are required for optimal formation of virus-like particles, highlighting the involvement of N, E and M in assembly of infectious particles. Altogether, our results highlight both similarities and dissimilarities in these events, as compared to other β-coronaviruses.

Published
2020

5. The interplays between Crimean-Congo hemorrhagic fever virus (CCHFV) M segment-encoded accessory proteins and structural proteins promote virus assembly and infectivity

Author

Natalia Freitas, Friedemann Weber, Solène Lerolle, François-Loïc Cosset, Gregory Neveu, Solène Denolly, Vincent Legros, Camille Lévy, Margot Enguehard, Eric Bergeron, Stephanie Devignot, Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), 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), Justus-Liebig-Universität Gießen (JLU), Centers for Disease Control and Prevention [Atlanta] (CDC), Centers for Disease Control and Prevention, Université de Lyon, VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), This work performed in the laboratory of FLC was supported by the French National Research Agency (ANR), the IDEXLYON (ANR-16-IDEX-0005) and the LabEx Ecofect (ANR-11-LABX-0048) of the 'Université de Lyon' (http://ecofect.universite-lyon.fr/), within the program 'Investissements d’Avenir' (ANR-11-IDEX-0007) operated by the ANR. VL received financial support from the 'IDEXLYON IMPULSION 2019' project (ANR-16-IDEX-0005) of the ‘‘Université de Lyon', within the program ‘‘Investissements d’Avenir' (ANR-16-IDEX-0005) and from the 'Global Health Impulsion 2020' project of VetAgro Sup. FW is supported by the CCHVaccine consortium that has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 732732, and by the Swedish Research Council (Vetenskapsrådet, VR) section Research Environment, Infection Biology (contract number 2018-05766)., ANR-16-IDEX-0005,IDEXLYON,IDEXLYON(2016), ANR-11-LABX-0048,ECOFECT,Dynamiques eco-évolutives des maladies infectieuses(2011), 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), Justus-Liebig-Universität Gießen = Justus Liebig University (JLU), Bodescot, Myriam, IDEXLYON - - IDEXLYON2016 - ANR-16-IDEX-0005 - IDEX - VALID, Dynamiques eco-évolutives des maladies infectieuses - - ECOFECT2011 - ANR-11-LABX-0048 - LABX - VALID, 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)

Subjects
Cell Membranes, Glycobiology, Golgi Apparatus, Biochemistry, Virions, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Biology (General), chemistry.chemical_classification, Infectivity, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0303 health sciences, Secretory Pathway, 030302 biochemistry & molecular biology, 3. Good health, Transport protein, Protein Transport, Cell Processes, Hemorrhagic Fever Virus, Crimean-Congo, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, symbols, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Cellular Structures and Organelles, Research Article, QH301-705.5, Immunology, Biology, Viral Structure, Transfection, Research and Analysis Methods, Microbiology, Virus, 03 medical and health sciences, symbols.namesake, Virology, Cell Line, Tumor, Genetics, Humans, Molecular Biology Techniques, Molecular Biology, Secretory pathway, 030304 developmental biology, Glycoproteins, Viral Structural Proteins, Virus Assembly, Biology and Life Sciences, Membrane Proteins, Protein Secretion, Proteins, Cell Biology, Golgi apparatus, RC581-607, Secretory protein, chemistry, Membrane protein, Parasitology, Immunologic diseases. Allergy, Glycoprotein, Gene Deletion
Abstract

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne orthonairovirus that has become a serious threat to the public health. CCHFV has a single-stranded, tripartite RNA genome composed of L, M, and S segments. Cleavage of the M polyprotein precursor generates the two envelope glycoproteins (GPs) as well as three secreted nonstructural proteins GP38 and GP85 or GP160, representing GP38 only or GP38 linked to a mucin-like protein (MLD), and a double-membrane-spanning protein called NSm. Here, we examined the relevance of each M-segment non-structural proteins in virus assembly, egress and infectivity using a well-established CCHFV virus-like-particle system (tc-VLP). Deletion of MLD protein had no impact on infectivity although it reduced by 60% incorporation of GPs into particles. Additional deletion of GP38 abolished production of infectious tc-VLPs. The loss of infectivity was associated with impaired Gc maturation and exclusion from the Golgi, showing that Gn is not sufficient to target CCHFV GPs to the site of assembly. Consistent with this, efficient complementation was achieved in cells expressing MLD-GP38 in trans with increased levels of preGc to Gc conversion, co-targeting to the Golgi, resulting in particle incorporation and restored infectivity. Contrastingly, a MLD-GP38 variant retained in the ER allowed preGc cleavage but failed to rescue miss-localization or infectivity. NSm deletion, conversely, did not affect trafficking of Gc but interfered with Gc processing, particle formation and secretion. NSm expression affected N-glycosylation of different viral proteins most likely due to increased speed of trafficking through the secretory pathway. This highlights a potential role of NSm in overcoming Golgi retention and facilitating CCHFV egress. Thus, deletions of GP38 or NSm demonstrate their important role on CCHFV particle production and infectivity. GP85 is an essential viral factor for preGc cleavage, trafficking and Gc incorporation into particles, whereas NSm protein is involved in CCHFV assembly and virion secretion., Author summary Orthonairoviruses, like the lethal Crimean-Congo hemorrhagic fever virus (CCHFV), encode secreted glycoproteins, such as GP38, in addition to virion envelope glycoproteins (Gn and Gc) that are processed by internal cleavage of the viral M segment encoded polyprotein. CCHFV MLD-GP38 proteins (GP160/GP85) also include an N-terminal domain encompassing a mucin-like protein that is released from GP38 by Furin. The protective effect of non-neutralizing monoclonal antibodies targeting GP38 against lethal CCHFV challenge previously highlighted the importance of GP38 in CCHFV replication. CCHFV also encodes a double-membrane-spanning protein (NSm) of unknown function, located between the Gn and Gc on the polyprotein. To investigate the roles of these so-called accessory proteins encoded by the CCHFV M-segment in virus formation and infectivity, we generated several M-segment deletion mutants and tested them in a CCHFV transcription-entry-competent virus-like particle (tc-VLP) system. Here, we demonstrate that GP38 is crucial for Gc biogenesis, interaction with Gn and trafficking to the Golgi, and that its deletion abrogates formation of infectious particles. We also show that NSm increases the rate of protein trafficking through the secretory pathway with altered N-glycosylation profiles that are advantageous for efficient virus release. These data advanced our understanding of GP38 and NSm roles and CCHFV-host interactions.

Published
2020
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6. Differentiation-dependent susceptibility of human muscle cells to Zika virus infection

Author

Gillian Butler-Browne, Jim Zoladek, Ingo Riederer, Quentin Giai Gianetto, Philippe Roingeard, Patricia Jeannin, Julien Burlaud-Gaillard, Pierre-Emmanuel Ceccaldi, Mariette Matondo, Valérie Choumet, Thibault Chaze, Vincent Legros, Vincent Mouly, Philippe V. Afonso, Antoine Gessain, Mariela-Natacha Gonzàlez, Epidémiologie et Physiopathologie des Virus Oncogènes (EPVO (UMR_3569 / U-Pasteur_3)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Plateforme IBISA de Microscopie Electronique [CHRU de Tours] (UNIV Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)-Université de Tours, Spectrométrie de Masse pour la Biologie – Mass Spectrometry for Biology (UTechS MSBio), Centre National de la Recherche Scientifique (CNRS)-Centre de Ressources et de Recherche Technologique - Center for Technological Resources and Research (C2RT), Institut Pasteur [Paris]-Institut Pasteur [Paris], Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Centre de recherche en myologie, Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Fundação Oswaldo Cruz (FIOCRUZ), Réseau International des Instituts Pasteur (RIIP), Environnement et Risques infectieux - Environment and Infectious Risks (ERI), Institut Pasteur [Paris], This work was supported by a Pasteur-Fiocruz grant. VL was supported by a fellowship from the 'Fondation pour la Recherche Médicale' (FRM), IR and MG by CNPq/Ciências sem Fronteiras program, CNPq/Brazilian National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM). FOCEM - Mercosur Structural Convergence Fund 03/11. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., 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), Epidémiologie et Physiopathologie des Virus Oncogènes / Oncogenic Virus Epidemiology and Pathophysiology (EPVO (UMR_3569 / U-Pasteur_3)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT), Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Pasteur [Paris] (IP), Matondo, Mariette, Institut Pasteur [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), UMRS974, Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche en Myologie, 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), and Fundação Oswaldo Cruz / Oswaldo Cruz Foundation (FIOCRUZ)

Subjects
Proteomics, Pulmonology, RC955-962, Apoptosis, Pathology and Laboratory Medicine, Zika virus, 0302 clinical medicine, Medical Conditions, Animal Cells, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Arctic medicine. Tropical medicine, MESH: Proteins, Chikungunya, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Zika Virus Infection, Stem Cells, MESH: Proteomics, 3. Good health, Medical Microbiology, Arboviral Infections, Viral Pathogens, Interferon Type I, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Public aspects of medicine, Cellular Types, MESH: Zika Virus, Microbiology, 03 medical and health sciences, Respiratory Disorders, MESH: Zika Virus Infection, Humans, Microbial Pathogens, MESH: Humans, Flaviviruses, MESH: Host-Pathogen Interactions, Public Health, Environmental and Occupational Health, Organisms, Biology and Life Sciences, Chikungunya Infection, Proteins, medicine.disease, Tropical Diseases, Virology, MESH: Cell Line, 030104 developmental biology, Biological Tissue, Interferon type I, Developmental Biology, 0301 basic medicine, RNA viruses, MESH: Cell Death, MESH: Interferon Type I, MESH: Muscle Cells, Viral Diseases, [SDV]Life Sciences [q-bio], Muscle Fibers, Skeletal, medicine.disease_cause, Virus Replication, Dengue fever, Myoblasts, Cytopathogenic Effect, Viral, Medicine and Health Sciences, Morphogenesis, Myocyte, Cytopathic effect, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Muscle Fibers, Skeletal, Cell Death, Myogenesis, Cell Differentiation, Muscle Differentiation, Infectious Diseases, Cell Processes, Viruses, Host-Pathogen Interactions, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Disease Susceptibility, Stem cell, RA1-1270, Pathogens, Anatomy, medicine.drug, Research Article, Neglected Tropical Diseases, MESH: Cell Differentiation, 030231 tropical medicine, Muscle Tissue, MESH: Disease Susceptibility, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Stem Cells, Biology, Cell Line, medicine, MESH: Myoblasts, Muscle Cells, MESH: Virus Replication, Cell Biology, Zika Virus, biology.organism_classification, MESH: Cytopathogenic Effect, Viral, Respiratory Infections
Abstract

Muscle cells are potential targets of many arboviruses, such as Ross River, Dengue, Sindbis, and chikungunya viruses, that may be involved in the physiopathological course of the infection. During the recent outbreak of Zika virus (ZIKV), myalgia was one of the most frequently reported symptoms. We investigated the susceptibility of human muscle cells to ZIKV infection. Using an in vitro model of human primary myoblasts that can be differentiated into myotubes, we found that myoblasts can be productively infected by ZIKV. In contrast, myotubes were shown to be resistant to ZIKV infection, suggesting a differentiation-dependent susceptibility. Infection was accompanied by a caspase-independent cytopathic effect, associated with paraptosis-like cytoplasmic vacuolization. Proteomic profiling was performed 24h and 48h post-infection in cells infected with two different isolates. Proteome changes indicate that ZIKV infection induces an upregulation of proteins involved in the activation of the Interferon type I pathway, and a downregulation of protein synthesis. This work constitutes the first observation of primary human muscle cells susceptibility to ZIKV infection, and differentiation-dependent restriction of infection from myoblasts to myotubes. Since myoblasts constitute the reservoir of stem cells involved in reparation/regeneration in muscle tissue, the infection of muscle cells and the viral-induced alterations observed here could have consequences in ZIKV infection pathogenesis., Author summary Muscle cells are potential targets of many arboviruses, such as Ross River, Dengue, Sindbis, and chikungunya viruses, and may be involved in the disease manifestation. During the recent outbreak of Zika virus (ZIKV), myalgia was one of the most frequently reported symptoms. We investigated the susceptibility of human muscle cells to ZIKV infection. Using an in vitro model of human muscle stem cells (myoblasts) that can be differentiated into differentiated muscle cells (myotubes), we found that myoblasts can be infected by ZIKV. In contrast, myotubes were shown to be resistant to ZIKV infection. Infection induced the death of infected cells. Protein levels 24h and 48h post-infection indicate that ZIKV infection induces an upregulation of proteins involved in the activation of the Interferon type I pathway, and a downregulation of protein synthesis. This work constitutes the first observation of primary human muscle cells susceptibility to ZIKV infection, muscle stem cells being susceptible while differentiated muscle cells are resistant. Since myoblasts constitute the reservoir of stem cells involved in reparation/regeneration in muscle tissue, the infection of muscle cells and the viral-induced alterations observed here could have consequences during ZIKV infection.

Published
2020
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7. Productive Infection of Mouse Mammary Glands and Human Mammary Epithelial Cells by Zika Virus

Author

Vincent Legros, Patricia Jeannin, Antoine Gessain, Mathieu Hubert, Pierre-Emmanuel Ceccaldi, Thomas Montange, Aurélie Chiche, Aurore Vidy, Epidémiologie et Physiopathologie des Virus Oncogènes / Oncogenic Virus Epidemiology and Pathophysiology (EPVO (UMR_3569 / U-Pasteur_3)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Plasticité cellulaire et Modélisation des Maladies / Cellular Plasticity and Disease Modelling, Institut Pasteur [Paris] (IP)-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), 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), This research received no external funding. M.H. was the recipient of a PhD fellowship from the French ministry of education and research, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], 030231 tropical medicine, lcsh:QR1-502, primary cells, Biology, Breast milk, Virus Replication, myoepithelial cells, Virus, lcsh:Microbiology, Article, dissemination, Zika virus, Cell Line, 03 medical and health sciences, Mice, luminal cells, 0302 clinical medicine, Pregnancy, Virology, Animals, Humans, mammary glands, Mammary Glands, Human, Fetus, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Milk, Human, Transmission (medicine), tropism, Myoepithelial cell, Epithelial Cells, Viral Load, biology.organism_classification, Infectious Disease Transmission, Vertical, 3. Good health, Viral Tropism, 030104 developmental biology, Infectious Diseases, Mammary Epithelium, RNA, Viral, Female, Viral load
Abstract

International audience; Zika virus (ZIKV) belongs to the large category of arboviruses. Surprisingly, several human-to-human transmissions of ZIKV have been notified, either following sexual intercourse or from the mother to fetus during pregnancy. Importantly, high viral loads have been detected in the human breast milk of infected mothers, and the existence of breastfeeding as a new mode of mother-to-child transmission of ZIKV was recently hypothesized. However, the maternal origin of infectious particles in breast milk is currently unknown. Here, we show that ZIKV disseminates to the mammary glands of infected mice after both systemic and local exposure with differential kinetics. Ex vivo, we demonstrate that primary human mammary epithelial cells were sensitive and permissive to ZIKV infection in this study. Moreover, by using in vitro models, we prove that mammary luminal-and myoepithelial-phenotype cell lines are both able to produce important virus progeny after ZIKV exposure. Our data suggest that the dissemination of ZIKV to the mammary glands and subsequent infection of the mammary epithelium could be one mechanism of viral excretion in human breast milk.

Published
2019
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8. Les enclos laténiens sont-ils toujours des fermes ?

Author

Ginette Auxiette, Estelle Pinard, François Malrain, Lydie Blondiau, Vincent Legros, Cyrille Chaidron, Histoire Archéologie Littérature des Mondes Anciens (HALMA) - UMR 8164 ( HALMA ), Ministère de la Culture et de la Communication ( MCC ) -Université de Lille-Centre National de la Recherche Scientifique ( CNRS ), Institut National de Recherches Archéologiques Préventives ( INRAP ), Institut national de recherches archéologiques préventives ( Inrap ), Archéologies et Sciences de l'Antiquité ( ArScAn ), Université Panthéon-Sorbonne ( UP1 ) -Université Paris Nanterre ( UPN ) -Ministère de la Culture et de la Communication ( MCC ) -Centre National de la Recherche Scientifique ( CNRS ), Maison de l'Archéologie et de l'Ethnologie à Nanterre - UMR 7041, UMR 8215 Trajectoires ( UMR 8215 ), Université Panthéon-Sorbonne ( UP1 ) -Centre National de la Recherche Scientifique ( CNRS ), Histoire Archéologie Littérature des Mondes Anciens - UMR 8164 (HALMA), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Ministère de la Culture (MC), Institut national de recherches archéologiques préventives (Inrap), Archéologies et Sciences de l'Antiquité (ArScAn), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris Nanterre (UPN)-Ministère de la Culture et de la Communication (MCC)-Centre National de la Recherche Scientifique (CNRS), Trajectoires - UMR 8215, Université Paris 1 Panthéon-Sorbonne (UP1)-Centre National de la Recherche Scientifique (CNRS), Histoire, Archéologie et Littérature des Mondes Anciens - UMR 8164 (HALMA), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris 8 Vincennes-Saint-Denis (UP8)-Université Paris Nanterre (UPN)-Ministère de la Culture et de la Communication (MCC)-Centre National de la Recherche Scientifique (CNRS), and Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris 8 Vincennes-Saint-Denis (UP8)-Université Paris Nanterre (UPN)-Ministère de la Culture et de la Communication (MCC)-Institut national de recherches archéologiques préventives (Inrap)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Archeology, faune, Iron Age, enclosure, activity, function, hierarchie, enclos, [SHS.ARCHEO]Humanities and Social Sciences/Archaeology and Prehistory, [ SHS.ARCHEO ] Humanities and Social Sciences/Archaeology and Prehistory, Tätigkeit, Eisenzeit, Umfriedung, Funktion, ferme, fonction, âge du Fer, activité, céramique, ComputingMilieux_MISCELLANEOUS
Abstract

Ziel ist es, von einigen Beispielen ausgehend, die Debatte über die Funktion der latènezeitlichen Umfriedungen zu beleben. Wenn eine Fundstätte eine Umfriedung aufweist, deren Gräben Gebäude und Strukturen umgeben, wird in den meisten Fallen eine landwirtschaftliche Funktion vorgeschlagen. Nun scheint es aber, dass diese Funktion nicht immer ausschliefilich zutrifft, und dass sie in einigen Fallen sogar ausgeschlossen werden kann. Folglich ist es angemessen, sich um neue Interpretierungen zu bemuhen, um versuchen der Vielf alt der gallischen Siedlungsstrukturen besser gerecht zu werden., This article proposes to renew the debate on the function of La Tène period enclosures on the basis of a series of examples. Where a site presents an enclosure with ditches delimiting buildings and structural features, the usual suggestion is that its function was agro-pastoral. However, it would appear that this function is not necessarily exclusive, and that in certain cases it may even be possible to eliminate this hypothesis. Hence the need to envisage new interpretations which would take the diversity of Gaulish habitats more fully into account., À partir de quelques exemples, le propos est de relancer le débat sur la fonction des enclos de la période laténienne. Une fonction agro-pastorale est la plus fréquemment proposée lorsqu'un site livre un enclos dont les fossés délimitent des bâtiments et des structures. Or, il apparaît que cette fonction n'est parfois pas exclusive et que dans certains cas, elle peut même être écartée. Dès lors, il convient de rechercher de nouvelles interprétations pour tenter de mieux rendre compte de la diversité des formes d'habitats gaulois., Malrain François, Blondiau Lydie, Chaidron Cyrille, Auxiette Ginette, Legros Vincent, Pinard Estelle. Les enclos laténiens sont-ils toujours des fermes ?. In: Revue archéologique de Picardie, n°3-4, 2007. pp. 17-55.

Published
2007

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