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1. Nebulized fusion inhibitory peptide protects cynomolgus macaques from measles virus infection

Author

Olivier Reynard, Claudia Gonzalez, Claire Dumont, Mathieu Iampietro, Marion Ferren, Sandrine Le Guellec, Lajoie Laurie, Cyrille Mathieu, Gabrielle Carpentier, Georges Roseau, Francesca T. Bovier, Yun Zhu, Deborah Le Pennec, Jérome Montharu, Amin Addetia, Alexander L. Greninger, Christopher A. Alabi, Elise Brisebard, Anne Moscona, Laurent Vecellio, Matteo Porotto, and Branka Horvat

Subjects
Science
Abstract

Despite the availability of a safe and effective vaccine, measles remains the leading cause of child death among vaccine-preventable diseases. In this work, authors utilised a cynomolgus macaque model of infection, and a mesh nebuliser administration approach, to show efficacy of their aerosolized lipopeptide fusion inhibitor against the measles virus.

Published
2022
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2. Hamster organotypic modeling of SARS-CoV-2 lung and brainstem infection

Author

Marion Ferren, Valérie Favède, Didier Decimo, Mathieu Iampietro, Nicole A. P. Lieberman, Jean-Luc Weickert, Rodolphe Pelissier, Magalie Mazelier, Olivier Terrier, Anne Moscona, Matteo Porotto, Alexander L. Greninger, Nadia Messaddeq, Branka Horvat, and Cyrille Mathieu

Subjects
Science
Abstract

Here, Ferren et al. isolate Syrian hamster brainstem and lung tissue to establish ex vivo culture systems to study SARS-CoV-2 local viral tropism, immune response and tissue pathology. Further, they provide evidence that these systems can be used for screening of anti-viral compounds.

Published
2021
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3. Hamster organotypic kidney culture model of early-stage SARS-CoV-2 infection highlights a two-step renal susceptibility

Author

Sophie R Shyfrin, Marion Ferren, Laure Perrin-Cocon, Maxime Espi, Xavier Charmetant, Manon Brailly, Didier Decimo, Mathieu Iampietro, Lola Canus, Branka Horvat, Vincent Lotteau, Pierre-Olivier Vidalain, Olivier Thaunat, and Cyrille Mathieu

Subjects
Biochemistry, QD415-436
Abstract

Kidney pathology is frequently reported in patients hospitalized with COVID-19, the pandemic disease caused by the Severe acute respiratory coronavirus 2 (SARS-CoV-2). However, due to a lack of suitable study models, the events occurring in the kidney during the earliest stages of infection remain unknown. We have developed hamster organotypic kidney cultures (OKCs) to study the early stages of direct renal infection. OKCs maintained key renal structures in their native three-dimensional arrangement. SARS-CoV-2 productively replicated in hamster OKCs, initially targeting endothelial cells and later disseminating into proximal tubules. We observed a delayed interferon response, markers of necroptosis and pyroptosis, and an early repression of pro-inflammatory cytokines transcription followed by a strong later upregulation. While it remains an open question whether an active replication of SARS-CoV-2 takes place in the kidneys of COVID-19 patients with AKI, our model provides new insights into the kinetics of SARS-CoV-2 kidney infection and can serve as a powerful tool for studying kidney infection by other pathogens and testing the renal toxicity of drugs.

Published
2022
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4. High Pathogenicity of Nipah Virus from Pteropus lylei Fruit Bats, Cambodia

Author

Maria Gaudino, Noémie Aurine, Claire Dumont, Julien Fouret, Marion Ferren, Cyrille Mathieu, Olivier Reynard, Viktor E. Volchkov, Catherine Legras-Lachuer, Marie-Claude Georges-Courbot, and Branka Horvat

Subjects
Nipah virus, henipavirus, emerging infection, Pteropus bats, fruit bats, spillover, Medicine, Infectious and parasitic diseases, RC109-216
Abstract

We conducted an in-depth characterization of the Nipah virus (NiV) isolate previously obtained from a Pteropus lylei bat in Cambodia in 2003 (CSUR381). We performed full-genome sequencing and phylogenetic analyses and confirmed CSUR381 is part of the NiV-Malaysia genotype. In vitro studies revealed similar cell permissiveness and replication of CSUR381 (compared with 2 other NiV isolates) in both bat and human cell lines. Sequence alignments indicated conservation of the ephrin-B2 and ephrin-B3 receptor binding sites, the glycosylation site on the G attachment protein, as well as the editing site in phosphoprotein, suggesting production of nonstructural proteins V and W, known to counteract the host innate immunity. In the hamster animal model, CSUR381 induced lethal infections. Altogether, these data suggest that the Cambodia bat-derived NiV isolate has high pathogenic potential and, thus, provide insight for further studies and better risk assessment for future NiV outbreaks in Southeast Asia.

Published
2020
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5. Early Permissiveness of Central Nervous System Cells to Measles Virus Infection Is Determined by Hyperfusogenicity and Interferon Pressure

Author

Marion Ferren, Alexandre Lalande, Mathieu Iampietro, Lola Canus, Didier Decimo, Denis Gerlier, Matteo Porotto, and Cyrille Mathieu

Subjects
measles virus, central nervous system infection, hyperfusogenicity, viral encephalitis, cell susceptibility, interferon treatment, Microbiology, QR1-502
Abstract

The cessation of measles virus (MeV) vaccination in more than 40 countries as a consequence of the COVID-19 pandemic is expected to significantly increase deaths due to measles. MeV can infect the central nervous system (CNS) and lead to lethal encephalitis. Substantial part of virus sequences recovered from patients’ brain were mutated in the matrix and/or the fusion protein (F). Mutations of the heptad repeat domain located in the C terminal (HRC) part of the F protein were often observed and were associated to hyperfusogenicity. These mutations promote brain invasion as a hallmark of neuroadaptation. Wild-type F allows entry into the brain, followed by limited spreading compared with the massive invasion observed for hyperfusogenic MeV. Taking advantage of our ex vivo models of hamster organotypic brain cultures, we investigated how the hyperfusogenic mutations in the F HRC domain modulate virus distribution in CNS cells. In this study, we also identified the dependence of neural cells susceptibility on both their activation state and destabilization of the virus F protein. Type I interferon (IFN-I) impaired mainly astrocytes and microglial cells permissiveness contrarily to neurons, opening a new way of consideration on the development of treatments against viral encephalitis.

Published
2023
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6. Activation of cGAS/STING pathway upon paramyxovirus infection

Author

Mathieu Iampietro, Claire Dumont, Cyrille Mathieu, Julia Spanier, Jonathan Robert, Aude Charpenay, Sébastien Dupichaud, Kévin P. Dhondt, Noémie Aurine, Rodolphe Pelissier, Marion Ferren, Stéphane Mély, Denis Gerlier, Ulrich Kalinke, and Branka Horvat

Subjects
immune system, molecular biology, Virology, Science
Abstract

Summary: During inflammatory diseases, cancer, and infection, the cGAS/STING pathway is known to recognize foreign or self-DNA in the cytosol and activate an innate immune response. Here, we report that negative-strand RNA paramyxoviruses, Nipah virus (NiV), and measles virus (MeV), can also trigger the cGAS/STING axis. Although mice deficient for MyD88, TRIF, and MAVS still moderately control NiV infection when compared with wild-type mice, additional STING deficiency resulted in 100% lethality, suggesting synergistic roles of these pathways in host protection. Moreover, deletion of cGAS or STING resulted in decreased type I interferon production with enhanced paramyxoviral infection in both human and murine cells. Finally, the phosphorylation and ubiquitination of STING, observed during viral infections, confirmed the activation of cGAS/STING pathway by NiV and MeV. Our data suggest that cGAS/STING activation is critical in controlling paramyxovirus infection and possibly represents attractive targets to develop countermeasures against severe disease induced by these pathogens.

Published
2021
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7. Molecular Features of the Measles Virus Viral Fusion Complex That Favor Infection and Spread in the Brain

Author

Cyrille Mathieu, Francesca T. Bovier, Marion Ferren, Nicole A. P. Lieberman, Camilla Predella, Alexandre Lalande, Vikas Peddu, Michelle J. Lin, Amin Addetia, Achchhe Patel, Victor Outlaw, Barbara Corneo, N. Valerio Dorrello, Thomas Briese, Diana Hardie, Branka Horvat, Anne Moscona, Alexander L. Greninger, and Matteo Porotto

Subjects
Microbiology, QR1-502
Abstract

Measles virus (MeV) infection can cause serious complications in immunocompromised individuals, including measles inclusion body encephalitis (MIBE). In some cases, MeV persistence and subacute sclerosing panencephalitis (SSPE), another severe central nervous system (CNS) complication, develop even in the face of a systemic immune response.

Published
2021
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8. Viral Entry Properties Required for Fitness in Humans Are Lost through Rapid Genomic Change during Viral Isolation

Author

Sho Iketani, Ryan C. Shean, Marion Ferren, Negar Makhsous, Dolly B. Aquino, Amedee des Georges, Bert Rima, Cyrille Mathieu, Matteo Porotto, Anne Moscona, and Alexander L. Greninger

Subjects
entry mechanisms, lung infection, metagenomics, parainfluenza virus, paramyxovirus, viral evolution, Microbiology, QR1-502
Abstract

IMPORTANCE Human parainfluenza virus 3 is an important cause of morbidity and mortality among infants, the immunocompromised, and the elderly. Using deep genomic sequencing of HPIV-3-positive clinical material and its subsequent viral isolate, we discover a number of known and novel coding mutations in the main HPIV-3 attachment protein HN during brief exposure to immortalized cells. These mutations significantly alter function of the fusion complex, increasing fusion promotion by HN as well as generally decreasing neuraminidase activity and increasing HN-receptor engagement. These results show that viruses may evolve rapidly in culture even during primary isolation of the virus and before the first passage and reveal features of fitness for humans that are obscured by rapid adaptation to laboratory conditions.

Published
2018
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9. Measles Encephalitis: Towards New Therapeutics

Author

Marion Ferren, Branka Horvat, and Cyrille Mathieu

Subjects
measles virus, central nervous system, tropism, treatments, Microbiology, QR1-502
Abstract

Measles remains a major cause of morbidity and mortality worldwide among vaccine preventable diseases. Recent decline in vaccination coverage resulted in re-emergence of measles outbreaks. Measles virus (MeV) infection causes an acute systemic disease, associated in certain cases with central nervous system (CNS) infection leading to lethal neurological disease. Early following MeV infection some patients develop acute post-infectious measles encephalitis (APME), which is not associated with direct infection of the brain. MeV can also infect the CNS and cause sub-acute sclerosing panencephalitis (SSPE) in immunocompetent people or measles inclusion-body encephalitis (MIBE) in immunocompromised patients. To date, cellular and molecular mechanisms governing CNS invasion are still poorly understood. Moreover, the known MeV entry receptors are not expressed in the CNS and how MeV enters and spreads in the brain is not fully understood. Different antiviral treatments have been tested and validated in vitro, ex vivo and in vivo, mainly in small animal models. Most treatments have high efficacy at preventing infection but their effectiveness after CNS manifestations remains to be evaluated. This review describes MeV neural infection and current most advanced therapeutic approaches potentially applicable to treat MeV CNS infection.

Published
2019
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10. High Pathogenicity of Nipah Virus from Pteropus lylei Fruit Bats, Cambodia

Author

Gaudino, Maria, Aurine, Noemie, Dumont, Claire, Fouret, Julien, Mathieu, Marion Ferren Cyrille, Reynard, Olivier, Volchkov, Viktor E., Legras-Lachuer, Catherine, Georges-Courbot, Marie-Claude, and Horvat, Branka

Subjects
Hamsters -- Genetic aspects -- Protection and preservation -- Analysis -- Health aspects, Cells (Biology) -- Genetic aspects -- Protection and preservation -- Analysis -- Health aspects, DNA sequencing -- Genetic aspects -- Protection and preservation -- Analysis -- Health aspects, Phylogeny -- Genetic aspects -- Protection and preservation -- Analysis -- Health aspects, Genomes -- Genetic aspects -- Protection and preservation -- Analysis -- Health aspects, Genomics -- Genetic aspects -- Protection and preservation -- Analysis -- Health aspects, Proteins -- Genetic aspects -- Protection and preservation -- Analysis -- Health aspects, Characterization, Health
Abstract

Nipah virus (NiV) is a zoonotic paramyxovirus that was first identified as the cause of an outbreak of encephalitis in humans in Malaysia and Singapore during 1998-1999 (1). Although NiV [...]

Published
2020
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11. Single-chain variable fragment antibody constructs neutralize measles virus infection in vitro and in vivo

Author

Fabrizio Angius, Branka Horvat, Stefan Niewiesk, Anne Moscona, Marion Ferren, Olivia Harder, Jennifer Drew-Bear, Tara C. Marcink, Matteo Porotto, N. Valerio Dorrello, Camilla Predella, Cyrille Mathieu, Francesca T. Bovier, Alexander L. Greninger, Mathieu, Cyrille, Ferren, Marion, Harder, Olivia, Bovier, Francesca T, Marcink, Tara C, Predella, Camilla, Angius, Fabrizio, Drew-Bear, Jennifer, Dorrello, N Valerio, Greninger, Alex L, Moscona, Anne, Niewiesk, Stefan, Horvat, Branka, Porotto, Matteo, 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), Columbia University [New York], Ohio State University [Columbus] (OSU), Università degli studi della Campania 'Luigi Vanvitelli' = University of the Study of Campania Luigi Vanvitelli, University of Washington [Seattle], Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Università degli studi della Campania 'Luigi Vanvitelli', 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
Immunology, Antibodies, Viral, Viral infection, Measles virus, 03 medical and health sciences, Text mining, In vivo, Single-Chain Variable Fragment Antibody, Correspondence, Humans, Immunology and Allergy, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0303 health sciences, biology, business.industry, 030302 biochemistry & molecular biology, biology.organism_classification, Virology, In vitro, 3. Good health, Infectious Diseases, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, business, Measles, Single-Chain Antibodies
Abstract

International audience; No abstract available

Published
2021

12. Organotypic modeling of SARS-CoV-2 lung and brainstem infection

Author

Mathieu Iampietro, Jean-Luc Weickert, Matteo Porotto, Anne Moscona, Rodolphe Pelissier, Didier Decimo, Nicole A P Lieberman, Magalie Mazelier, Branka Horvat, Cyrille Mathieu, Nadia Messaddeq, Alexander L. Greninger, Valérie Favede, Olivier Terrier, Marion Ferren, 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), University of Washington [Seattle], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Columbia University Medical Center (CUMC), Columbia University [New York], University of the Study of Campania Luigi Vanvitelli, 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), and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0303 health sciences, Programmed cell death, Innate immune system, Lung, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, 030306 microbiology, business.industry, [SDV]Life Sciences [q-bio], Virus, 3. Good health, Pathogenesis, 03 medical and health sciences, medicine.anatomical_structure, Interferon, Immunology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Medicine, Brainstem, business, Tropism, 030304 developmental biology, medicine.drug
Abstract

SARS-CoV-2 has caused a global pandemic of Covid-19 since its emergence in December 2019. The infection causes a severe acute respiratory syndrome and may also lead to central nervous system infection and neurological sequelae. We developed and characterized two new organotypic cultures from hamster brainstem and lung tissues that offer the unique opportunity to study the early steps of the pathogenesis and screening of antivirals. Using these models, we validated the early tropism of the virus in the lung and demonstrated that SARS-CoV2 can infect brainstem and cerebellum, mainly by targeting granular neurons. Viral infection induced specific interferon and innate immune responses with patterns specific to each organ along with apoptotic, necroptotic, and pyroptotic cell death. Overall, our data illustrate the potential of rapidly modeling complex tissue level interactions of viral infection in a newly emerged virus.

Published
2021

13. Measles fusion complexes from central nervous system clinical isolates: decreased interaction between hemagglutinin and fusion proteins

Author

Decker Ar, Matteo Porotto, A. Moscona, Eric M. Jurgens, Marion Ferren, Tara C. Marcink, Nascimento Figueira T, Cyrille Mathieu, Francesca T. Bovier, 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), Columbia University [New York], University of the Study of Campania Luigi Vanvitelli, Weill Medical College of Cornell University [New York], Mathieu, Cyrille, 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
[SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0303 health sciences, biology, 030306 microbiology, Wild type, Hemagglutinin (influenza), medicine.disease, biology.organism_classification, Fusion protein, Virology, Subacute sclerosing panencephalitis, Virus, 3. Good health, Measles virus, 03 medical and health sciences, Viral entry, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, medicine, biology.protein, Receptor, 030304 developmental biology
Abstract

Measles virus (MeV) viral entry is mediated by a fusion complex comprised of a receptor binding protein (hemagglutinin, H) and a fusion protein (F). The wild type H/F complex requires interaction with specific proteinaceous receptors (CD150/SLAM and nectin-4) in order to be activated. In contrast the H/F complexes isolated from viruses infecting the central nervous system (CNS) do not require a specific receptor. A single amino acid change in the F protein (L454W) was previously identified in two patients with lethal sequelae of MeV CNS infection, and the F bearing this mutation mediates fusion even without the H protein. We show here that viruses bearing the L454W fusion complex are less efficient than wt virus at targeting receptor expressing cells and that this defect is associated with a decreased interaction between the H and the F proteins.ImportanceMeasles (Mev) infection can cause serious complications including measles inclusion body encephalitis (MIBE) and subacute sclerosing panencephalitis (SSPE). MIBE and SSPE are relatively rare but lethal. We have shown that the fusion complex of CNS adapted clinical samples can spread in the absence of known receptor. We now provide evidence that HRC mutations leading to CNS adaptation come at a cost to the efficiency of viral entry.One Sentence SummaryMeasles CNS adapted fusion complexes have altered H/F interaction.

Published
2021

14. Molecular Features of the Measles Virus Viral Fusion Complex That Favor Infection and Spread in the Brain

Author

Branka Horvat, Camilla Predella, Diana Hardie, Nicole A. P. Lieberman, Achchhe Patel, Michelle J. Lin, Anne Moscona, Alexander L. Greninger, Barbara Corneo, Thomas Briese, Cyrille Mathieu, Francesca T. Bovier, Victor K. Outlaw, Vikas Peddu, Matteo Porotto, Amin Addetia, Alexandre Lalande, Marion Ferren, N. Valerio Dorrello, 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), Columbia University [New York], University of the Study of Campania Luigi Vanvitelli, University of Washington [Seattle], University of Wisconsin-Madison, University of Cape Town, 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), Mathieu, Cyrille, Bovier, Francesca T, Ferren, Marion, Lieberman, Nicole A P, Predella, Camilla, Lalande, Alexandre, Peddu, Vika, Lin, Michelle J, Addetia, Amin, Patel, Achchhe, Outlaw, Victor, Corneo, Barbara, Dorrello, N Valerio, Briese, Thoma, Hardie, Diana, Horvat, Branka, Moscona, Anne, Greninger, Alexander L, and Porotto, Matteo

Subjects
Male, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, host-pathogen interaction, medicine.disease_cause, Mice, viral evolution, Central Nervous System Diseases, central nervous system infection, Chlorocebus aethiops, Neurons, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0303 health sciences, Mutation, biology, 030302 biochemistry & molecular biology, Brain, QR1-502, 3. Good health, Organoids, medicine.anatomical_structure, Viral evolution, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, Research Article, Induced Pluripotent Stem Cells, Central nervous system, Microbiology, Subacute sclerosing panencephalitis, Virus, Measles virus, 03 medical and health sciences, Immune system, Virology, medicine, Animals, Humans, Vero Cells, 030304 developmental biology, fungi, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.disease, biology.organism_classification, Fusion protein, HEK293 Cells, Amino Acid Substitution, Metagenomics, viral fusion, Viral Fusion Proteins, Measles
Abstract

Measles virus (MeV) bearing a single amino acid change in the fusion protein (F)-L454W-was isolated from two patients who died of MeV central nervous system (CNS) infection. This mutation in F confers an advantage over wild-type virus in the CNS, contributing to disease in these patients. Using murine ex vivo organotypic brain cultures and human induced pluripotent stem cell-derived brain organoids, we show that CNS adaptive mutations in F enhance the spread of virus ex vivo. The spread of virus in human brain organoids is blocked by an inhibitory peptide that targets F, confirming that dissemination in the brain tissue is attributable to F. A single mutation in MeV F thus alters the fusion complex to render MeV more neuropathogenic. IMPORTANCE Measles virus (MeV) infection can cause serious complications in immunocompromised individuals, including measles inclusion body encephalitis (MIBE). In some cases, MeV persistence and subacute sclerosing panencephalitis (SSPE), another severe central nervous system (CNS) complication, develop even in the face of a systemic immune response. Both MIBE and SSPE are relatively rare but lethal. It is unclear how MeV causes CNS infection. We introduced specific mutations that are found in MIBE or SSPE cases into the MeV fusion protein to test the hypothesis that dysregulation of the viral fusion complex-comprising F and the receptor binding protein, H-allows virus to spread in the CNS. Using metagenomic, structural, and biochemical approaches, we demonstrate that altered fusion properties of the MeV H-F fusion complex permit MeV to spread in brain tissue.

Published
2021

15. Abstracts (DOI: jamp.2021.ab01.abstracts)

Author

M. Iampietro, Branka Horvat, Laurent Vecellio, Marion Ferren, Matteo Porotto, Anne Moscona, Maria Cabrera, Sandrine Le Guellec, C. Dumont, Cyrille Mathieu, G. Chantrel, 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), 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 - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), 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)

Subjects
Pulmonary and Respiratory Medicine, Lung, Inhalation, business.industry, Transmission (medicine), Pharmaceutical Science, medicine.disease, 030226 pharmacology & pharmacy, Virology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, 030228 respiratory system, Viral entry, In vivo, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Medicine, Pharmacology (medical), Respiratory system, business, Encephalitis, ComputingMilieux_MISCELLANEOUS, Respiratory tract
Abstract

Introduction: Nipah virus (NiV) is a recently emerged zoonotic paramyxovirus, capable of inter-human transmission and listed byWHO among the top eight emerging pathogens, based on the probability of causing severe outbreaks and a pandemic potential. In humans, NiV induces acute respiratory distress and encephalitis with a lethality of 40-100%.Anovel antiviral approach, based on peptideswhich interferewith the fusion of NiV with host cells has been recently developed. Research hypothesis: The project aims to develop a new approach to administer aerosolized peptides capable of inhibiting respiratory NiV infection, which may be applied to the other respiratory viruses using similar fusion mechanism for viral entry. Methods: We have developed an inhalation strategy using nebulized antiviral peptide in African Green Monkey (AGM), an animal model shown to well reproduce human NiV infection. Results and discussion: A customized nebuliser with a specific mesh size and interface to produce an aerosol of peptides while ensuring the upkeep of >90% of antiviral activity after nebulisation was assessed. Lung deposition was measured by in vivo scintigraphy (8-16% in terms of nebulizer charge). Toxicology analysis in AGM demonstrated the absence of adverse lung findings from nebulised peptides after several consecutive administrations of 10 min. Immunofluorescence assays, using peptide specific antibodies on lung slices, revealed the presence of peptides along the respiratory tract 24 h after administration. Conclusion: Developed nebulisers are now ready for the first proof-of-concept study with the infectious NiV in a Biosafety level 4 laboratory. The results may open new perspectives for antiviral prevention against respiratory viruses and the strategy could be further extended to the ongoing SARS-CoV-2 outbreak (funded by DGAANR-Astrid-Maturation).

Published
2021

16. Activation of cGAS/STING pathway upon paramyxovirus infection

Author

Cyrille Mathieu, Marion Ferren, Branka Horvat, Julia Spanier, Aude Charpenay, Mathieu Iampietro, Claire Dumont, Sébastien Dupichaud, Noémie Aurine, Rodolphe Pelissier, Stéphane Mély, Kévin P. Dhondt, Denis Gerlier, Ulrich Kalinke, Jonathan Robert, 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), Centre for Experimental and Clinical Infection Research [Hanover] (TWINCORE), Laboratoire P4 - Jean Mérieux, Centre Européen de Virologie/Immunologie-Institut National de la Santé et de la Recherche Médicale (INSERM), Mathieu, Cyrille, 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 ANR-18-CE11-0014,NiPah-C,Structure et fonctions de la protéine C du virus Nipah(2018)

Subjects
Science, Biology, Article, Measles virus, 03 medical and health sciences, 0302 clinical medicine, Ubiquitin, Virology, molecular biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0303 health sciences, Innate immune system, RNA, biology.organism_classification, eye diseases, 3. Good health, Sting, Cytosol, immune system, TRIF, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology.protein, Phosphorylation, 030217 neurology & neurosurgery
Abstract

Summary During inflammatory diseases, cancer, and infection, the cGAS/STING pathway is known to recognize foreign or self-DNA in the cytosol and activate an innate immune response. Here, we report that negative-strand RNA paramyxoviruses, Nipah virus (NiV), and measles virus (MeV), can also trigger the cGAS/STING axis. Although mice deficient for MyD88, TRIF, and MAVS still moderately control NiV infection when compared with wild-type mice, additional STING deficiency resulted in 100% lethality, suggesting synergistic roles of these pathways in host protection. Moreover, deletion of cGAS or STING resulted in decreased type I interferon production with enhanced paramyxoviral infection in both human and murine cells. Finally, the phosphorylation and ubiquitination of STING, observed during viral infections, confirmed the activation of cGAS/STING pathway by NiV and MeV. Our data suggest that cGAS/STING activation is critical in controlling paramyxovirus infection and possibly represents attractive targets to develop countermeasures against severe disease induced by these pathogens., Graphical abstract, Highlights • RNA sensors are insufficient for the effective control of paramyxovirus infection • STING adaptor protein is involved in controlling Nipah virus infection in mice • cGAS/STING axis is primordial for optimal production of IFN-I against NiV and MeV • STING protein can be activated during infections by RNA viruses, Immune system; Molecular biology; Virology

Published
2021

17. Interféron de type I et sélectivité de l’infection des cellules du système nerveux central par le virus de la rougeole

Author

Branka Horvat, Marion Ferren, Cyrille Mathieu, Denis Gerlier, 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), 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), Sciences, EDP, 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), 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)

Subjects
[SDV] Life Sciences [q-bio], 0303 health sciences, 03 medical and health sciences, 030306 microbiology, [SDV]Life Sciences [q-bio], General Medicine, Biology, Molecular biology, General Biochemistry, Genetics and Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

International audience; No abstract available

Published
2021

18. High Pathogenicity of Nipah Virus from Pteropus lylei Fruit Bats, Cambodia

Author

Julien Fouret, Olivier Reynard, Marion Ferren, Cyrille Mathieu, Claire Dumont, Maria Gaudino, Viktor E. Volchkov, Marie Claude Georges-Courbot, Catherine Legras-Lachuer, Branka Horvat, Noémie Aurine, 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), Viroscan3D SAS [Lyon, France], Laboratoire d'Ecologie Microbienne - UMR 5557 (LEM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Biologie des Infections Virales Émergentes - Biology of Emerging Viral Infections (UBIVE), 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], This work was supported by LABEX ECOFECT (ANR-11-LABX-0048) of Lyon University, within the program Investissements d'Avenir (ANR-11-IDEX-0007) operated by the French National Research Agency, ANR-18-CE11-0014-02, Aviesan Sino-French Agreement on Nipah Virus Study, and the International Division of the Pasteur Institut in Paris (Actions Concertées Inter-Pasteurienne). J.F. was supported by the doctoral fellowship CIFRE-Défense operated by the Direction Générale de l’Armement., We thank Jean-Marc Reynes and Pasteur Institut staff for providing us with the NiV Cambodia isolate and Doris Preininger, Anton Weissenbacher, and Tiergarten Schönbrunn for P. giganteus bat sampling. We thank Amelia Charlotte Coggon for English proofreading of the manuscript, and we also thank François Enchéry, Kévin Dhondt, Mathieu Iampietro, Sylvain Baize, and Géraldine Gourru-Lesimple for help initiating and finalizing this work., ANR-11-LABX-0048,ECOFECT,Dynamiques eco-évolutives des maladies infectieuses(2011), ANR-11-IDEX-0007,Avenir L.S.E.,PROJET AVENIR LYON SAINT-ETIENNE(2012), Mathieu, Cyrille, Dynamiques eco-évolutives des maladies infectieuses - - ECOFECT2011 - ANR-11-LABX-0048 - LABX - VALID, PROJET AVENIR LYON SAINT-ETIENNE - - Avenir L.S.E.2011 - ANR-11-IDEX-0007 - IDEX - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Structure et fonctions de la protéine C du virus Nipah - - NiPah-C2018 - ANR-18-CE11-0014 - AAPG2018 - VALID, Immunobiologie des infections virales – Immunobiology of Viral Infections (IbIV), 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), Virpath-Grippe, de l'émergence au contrôle -- Virpath-Influenza, from emergence to control (Virpath), Bases moléculaires de la pathogénicité virale – Molecular Basis of Viral Pathogenicity (BMPV), 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), This work was supported by LABEX ECOFECT (ANR-11-LABX-0048) of Lyon University, within the program Investissements d’Avenir (ANR-11-IDEX-0007) operated by the French National Research Agency, ANR-18-CE11-0014-02, Aviesan Sino-French Agreement on Nipah Virus Study, and the International Division of the Institut Pasteur in Paris (Actions Concertées Inter-Pasteurienne). J.F. was supported by the doctoral fellowship CIFRE-Défense operated by the Direction Générale de l’Armement., ANR-11-IDEX-0007,Avenir L.S.E.,PROJET AVENIR LYON SAINT-ETIENNE(2011), ANR-18-CE11-0014,NiPah-C,Structure et fonctions de la protéine C du virus Nipah(2018), 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], 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 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
Permissiveness, Epidemiology, lcsh:Medicine, Nipah virus, Pteropus lylei, Pteropus bats, 0302 clinical medicine, Chiroptera, Genotype, pathogenicity, 030212 general & internal medicine, Phylogeny, CSUR381, Henipavirus Infections, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, fruit bats, Phylogenetic tree, biology, sequencing, High Pathogenicity of Nipah Virus from Pteropus lylei Fruit Bats, Cambodia, phosphoprotein, 3. Good health, Infectious Diseases, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, RNA, Viral, Cambodia, Henipavirus, Microbiology (medical), henipavirus, spillover, 030231 tropical medicine, Genome, Viral, Real-Time Polymerase Chain Reaction, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, Phylogenetics, Animals, Humans, lcsh:RC109-216, viruses, emerging infection, Whole genome sequencing, Whole Genome Sequencing, Research, phylogenetic analysis, animal model, lcsh:R, Outbreak, biology.organism_classification, Virology, zoonoses, hamster, NiV-Malaysia genotype
Abstract

International audience; We conducted an in-depth characterization of the Nipah virus (NiV) isolate previously obtained from a Pteropus lylei bat in Cambodia in 2003 (CSUR381). We performed full-genome sequencing and phylogenetic analyses and confirmed CSUR381 is part of the NiV-Malaysia genotype. In vitro studies revealed similar cell permissiveness and replication of CSUR381 (compared with 2 other NiV isolates) in both bat and human cell lines. Sequence alignments indicated conservation of the ephrin-B2 and ephrin-B3 receptor binding sites, the glycosylation site on the G attachment protein, as well as the editing site in phosphoprotein, suggesting production of nonstructural proteins V and W, known to counteract the host innate immunity. In the hamster animal model, CSUR381 induced lethal infections. Altogether, these data suggest that the Cambodia bat-derived NiV isolate has high pathogenic potential and, thus, provide insight for further studies and better risk assessment for future NiV outbreaks in Southeast Asia.

Published
2020

19. Measles Virus Bearing Measles Inclusion Body Encephalitis-Derived Fusion Protein Is Pathogenic after Infection via the Respiratory Route

Author

Debora Stelitano, Sudipta Biswas, Claire Dumont, Eric M. Jurgens, Branka Horvat, Matteo Porotto, Takao Hashiguchi, Cyrille Mathieu, Diana Hardie, Marion Ferren, Olivia Harder, Anne Moscona, Silvia Madeddu, Stefan Niewiesk, Dayna Schwartz, Giuseppina Sanna, Ksenia Rybkina, Immunobiologie des infections virales – Immunobiology of Viral Infections (IbIV), 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 universitaire de formation des maîtres - Centre Val de Loire (IUFM Centre Val-de-Loire), Université d'Orléans (UO), Columbia University Irving Medical Center (CUIMC), National Health Laboratory Service, National Institute for Communicable Diseases [Johannesburg] (NICD), Institut NeuroMyoGène (INMG), 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), College of Veterinary Medicine [Colombus], Ohio State University [Columbus] (OSU), 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
Central Nervous System, Immunology, Mutation, Missense, Mice, Transgenic, Virus Replication, Microbiology, Subacute sclerosing panencephalitis, Virus, Inclusion Bodies, Viral, Measles virus, Mice, 03 medical and health sciences, Immune system, Virology, Chlorocebus aethiops, medicine, Animals, Humans, Encephalitis, Viral, Sigmodontinae, Cotton rat, Lung, Vero Cells, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Cell fusion, biology, 030306 microbiology, medicine.disease, biology.organism_classification, Fusion protein, Virus-Cell Interactions, 3. Good health, Disease Models, Animal, Amino Acid Substitution, Insect Science, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Viral Fusion Proteins, Encephalitis, Measles
Abstract

A clinical isolate of measles virus (MeV) bearing a single amino acid alteration in the viral fusion protein (F; L454W) was previously identified in two patients with lethal sequelae of MeV central nervous system (CNS) infection. The mutation dysregulated the viral fusion machinery so that the mutated F protein mediated cell fusion in the absence of known MeV cellular receptors. While this virus could feasibly have arisen via intrahost evolution of the wild-type (wt) virus, it was recently shown that the same mutation emerged under the selective pressure of small-molecule antiviral treatment. Under these conditions, a potentially neuropathogenic variant emerged outside the CNS. While CNS adaptation of MeV was thought to generate viruses that are less fit for interhost spread, we show that two animal models can be readily infected with CNS-adapted MeV via the respiratory route. Despite bearing a fusion protein that is less stable at 37°C than the wt MeV F, this virus infects and replicates in cotton rat lung tissue more efficiently than the wt virus and is lethal in a suckling mouse model of MeV encephalitis even with a lower inoculum. Thus, either during lethal MeV CNS infection or during antiviral treatment in vitro, neuropathogenic MeV can emerge, can infect new hosts via the respiratory route, and is more pathogenic (at least in these animal models) than wt MeV. IMPORTANCE Measles virus (MeV) infection can be severe in immunocompromised individuals and lead to complications, including measles inclusion body encephalitis (MIBE). In some cases, MeV persistence and subacute sclerosing panencephalitis (SSPE) occur even in the face of an intact immune response. While they are relatively rare complications of MeV infection, MIBE and SSPE are lethal. This work addresses the hypothesis that despite a dysregulated viral fusion complex, central nervous system (CNS)-adapted measles virus can spread outside the CNS within an infected host.

Published
2019

20. Analysis of a Subacute Sclerosing Panencephalitis Genotype B3 Virus from the 2009-2010 South African Measles Epidemic Shows That Hyperfusogenic F Proteins Contribute to Measles Virus Infection in the Brain

Author

Alexandre Lalande, Anne Moscona, Diana Hardie, Ksenia Rybkina, Heidi Smuts, Cyrille Mathieu, Debora Stelitano, Matteo Porotto, Fabrizio Angius, Branka Horvat, Brian Eley, Marion Ferren, Jo M. Wilmshurst, Takao Hashiguchi, Columbia University Medical Center (CUMC), Columbia University [New York], 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), Immunobiologie des infections virales – Immunobiology of Viral Infections (IbIV), 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), 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), 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), 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 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)

Subjects
Male, Genotype, Immunology, Biology, Giant Cells, Microbiology, Measles, Subacute sclerosing panencephalitis, Virus, Measles virus, South Africa, 03 medical and health sciences, Virology, Chlorocebus aethiops, medicine, Animals, Humans, Epidemics, Receptor, Vero Cells, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Neurons, 0303 health sciences, Syncytium, 030302 biochemistry & molecular biology, Brain, medicine.disease, biology.organism_classification, Fusion protein, Virus-Cell Interactions, 3. Good health, HEK293 Cells, Amino Acid Substitution, Ectodomain, Insect Science, Mutation, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, Subacute Sclerosing Panencephalitis, Cell Adhesion Molecules, Viral Fusion Proteins
Abstract

During a measles virus (MeV) epidemic in 2009 in South Africa, measles inclusion body encephalitis (MIBE) was identified in several HIV-infected patients. Years later, children are presenting with subacute sclerosing panencephalitis (SSPE). To investigate the features of established MeV neuronal infections, viral sequences were analyzed from brain tissue samples of a single SSPE case and compared with MIBE sequences previously obtained from patients infected during the same epidemic. Both the SSPE and the MIBE viruses had amino acid substitutions in the ectodomain of the F protein that confer enhanced fusion properties. Functional analysis of the fusion complexes confirmed that both MIBE and SSPE F protein mutations promoted fusion with less dependence on interaction by the viral receptor-binding protein with known MeV receptors. While the SSPE F required the presence of a homotypic attachment protein, MeV H, in order to fuse, MIBE F did not. Both F proteins had decreased thermal stability compared to that of the corresponding wild-type F protein. Finally, recombinant viruses expressing MIBE or SSPE fusion complexes spread in the absence of known MeV receptors, with MIBE F-bearing viruses causing large syncytia in these cells. Our results suggest that alterations to the MeV fusion complex that promote fusion and cell-to-cell spread in the absence of known MeV receptors is a key property for infection of the brain. IMPORTANCE Measles virus can invade the central nervous system (CNS) and cause severe neurological complications, such as MIBE and SSPE. However, mechanisms by which MeV enters the CNS and triggers the disease remain unclear. We analyzed viruses from brain tissue of individuals with MIBE or SSPE, infected during the same epidemic, after the onset of neurological disease. Our findings indicate that the emergence of hyperfusogenic MeV F proteins is associated with infection of the brain. We also demonstrate that hyperfusogenic F proteins permit MeV to enter cells and spread without the need to engage nectin-4 or CD150, known receptors for MeV that are not present on neural cells.

Published
2019

21. Authentic modeling of human respiratory virus infection in human pluripotent stem cell-derived lung organoids

Author

Marion Ferren, Negar Makhsous, Thomas Briese, Bert K. Rima, Matteo Porotto, Alexander L. Greninger, Yik Siu, Ya-Wen Chen, Anne Moscona, Hans-Willem Snoeck, Porotto, M., Ferren, M., Chen, Y. -W., Siu, Y., Makhsous, N., Rima, B., Briese, T., Greninger, A. L., Snoeck, H. -W., and Moscona, A.

Subjects
Viral pathogenesis, viruses, 0302 clinical medicine, Tissue infection model, Induced pluripotent stem cell, Lung, Cells, Cultured, 0303 health sciences, Cell Differentiation, respiratory system, QR1-502, 3. Good health, Organoids, Human Parainfluenza Virus, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Respiratory virus, Research Article, Pluripotent Stem Cells, Lung organoid, parainfluenza virus, Genome, Viral, Biology, Respirovirus Infections, lung organoids, Microbiology, Virus, Host-Microbe Biology, Measles virus, 03 medical and health sciences, respiratory viruses, Virology, medicine, Humans, Viral shedding, 030304 developmental biology, Whole Genome Sequencing, Respiratory viruse, Infant, Virus Internalization, Editor's Pick, biology.organism_classification, Parainfluenza Virus 3, Human, respiratory tract diseases, Alveolar Epithelial Cells, Respiratory Syncytial Virus, Human, Parainfluenza viru
Abstract

Respiratory viruses are among the first pathogens encountered by young children, and the significant impact of these viral infections on the developing lung is poorly understood. Circulating viruses are suited to the environment of the human lung and are different from those of viruses grown in cultured cells. We modeled respiratory virus infections that occur in children or infect the distal lung using lung organoids that represent the entire developing infant lung. These 3D lung organoids, derived from human pluripotent stem cells, develop into branching airway and alveolar structures and provide a tissue environment that maintains the authentic viral genome. The lung organoids can be genetically engineered prior to differentiation, thereby generating tissues bearing or lacking specific features that may be relevant to viral infection, a feature that may have utility for the study of host-pathogen interaction for a range of lung pathogens., Infectious viruses so precisely fit their hosts that the study of natural viral infection depends on host-specific mechanisms that affect viral infection. For human parainfluenza virus 3, a prevalent cause of lower respiratory tract disease in infants, circulating human viruses are genetically different from viruses grown in standard laboratory conditions; the surface glycoproteins that mediate host cell entry on circulating viruses are suited to the environment of the human lung and differ from those of viruses grown in cultured cells. Polarized human airway epithelium cultures have been used to represent the large, proximal airways of mature adult airways. Here we modeled respiratory virus infections that occur in children or infect the distal lung using lung organoids that represent the entire developing infant lung. These 3D lung organoids derived from human pluripotent stem cells contain mesoderm and pulmonary endoderm and develop into branching airway and alveolar structures. Whole-genome sequencing analysis of parainfluenza viruses replicating in the organoids showed maintenance of nucleotide identity, suggesting that no selective pressure is exerted on the virus in this tissue. Infection with parainfluenza virus led to viral shedding without morphological changes, while respiratory syncytial virus infection induced detachment and shedding of infected cells into the lung organoid lumens, reminiscent of parainfluenza and respiratory syncytial virus in human infant lungs. Measles virus infection, in contrast, induced syncytium formation. These human stem cell-derived lung organoids may serve as an authentic model for respiratory viral pathogenesis in the developing or infant lung, recapitulating respiratory viral infection in the host.

Published
2019

22. Viral Entry Properties Required for Fitness in Humans Are Lost through Rapid Genomic Change during Viral Isolation

Author

Marion Ferren, Negar Makhsous, Dolly B. Aquino, Ryan C. Shean, Matteo Porotto, Sho Iketani, Anne Moscona, Alexander L. Greninger, Bert K. Rima, Amedee des Georges, Cyrille Mathieu, 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), 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), 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), Iketani, Sho, Shean, Ryan C., Ferren, Marion, Makhsous, Negar, Aquino, Dolly B., Georges, Amedee de, Rima, Bert, Mathieu, Cyrille, Porotto, Matteo, Moscona, Anne, and Greninger, Alexander L.

Subjects
0301 basic medicine, Nonsynonymous substitution, Virus Cultivation, Entry mechanism, parainfluenza virus, 030106 microbiology, DNA Mutational Analysis, entry mechanisms, Adaptation, Biological, viral fitness, Paramyxoviru, Genome, Viral, Biology, Microbiology, Respirovirus Infections, Virus, 03 medical and health sciences, Metagenomic, viral evolution, paramyxovirus, Viral entry, Virology, Humans, Serial Passage, Gene, ComputingMilieux_MISCELLANEOUS, metagenomics, lung infection, Viral fitne, Virus Internalization, Fusion protein, Phenotype, QR1-502, 3. Good health, Parainfluenza Virus 3, Human, Human Parainfluenza Virus, 030104 developmental biology, Viral evolution, Mutation, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Genetic Fitness, viral fusion, Parainfluenza viru, Research Article
Abstract

IMPORTANCE Human parainfluenza virus 3 is an important cause of morbidity and mortality among infants, the immunocompromised, and the elderly. Using deep genomic sequencing of HPIV-3-positive clinical material and its subsequent viral isolate, we discover a number of known and novel coding mutations in the main HPIV-3 attachment protein HN during brief exposure to immortalized cells. These mutations significantly alter function of the fusion complex, increasing fusion promotion by HN as well as generally decreasing neuraminidase activity and increasing HN-receptor engagement. These results show that viruses may evolve rapidly in culture even during primary isolation of the virus and before the first passage and reveal features of fitness for humans that are obscured by rapid adaptation to laboratory conditions., Human parainfluenza viruses cause a large burden of human respiratory illness. While much research relies upon viruses grown in cultured immortalized cells, human parainfluenza virus 3 (HPIV-3) evolves in culture. Cultured viruses differ in their properties compared to clinical strains. We present a genome-wide survey of HPIV-3 adaptations to culture using metagenomic next-generation sequencing of matched pairs of clinical samples and primary culture isolates (zero passage virus). Nonsynonymous changes arose during primary viral isolation, almost entirely in the genes encoding the two surface glycoproteins—the receptor binding protein hemagglutinin-neuraminidase (HN) or the fusion protein (F). We recovered genomes from 95 HPIV-3 primary culture isolates and 23 HPIV-3 strains directly from clinical samples. HN mutations arising during primary viral isolation resulted in substitutions at HN’s dimerization/F-interaction site, a site critical for activation of viral fusion. Alterations in HN dimer interface residues known to favor infection in culture occurred within 4 days (H552 and N556). A novel cluster of residues at a different face of the HN dimer interface emerged (P241 and R242) and imply a role in HPIV-3-mediated fusion. Functional characterization of these culture-associated HN mutations in a clinical isolate background revealed acquisition of the fusogenic phenotype associated with cultured HPIV-3; the HN-F complex showed enhanced fusion and decreased receptor-cleaving activity. These results utilize a method for identifying genome-wide changes associated with brief adaptation to culture to highlight the notion that even brief exposure to immortalized cells may affect key viral properties and underscore the balance of features of the HN-F complex required for fitness by circulating viruses.

Published
2018
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