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1. Alphavirus nsP3 organizes into tubular scaffolds essential for infection and the cytoplasmic granule architecture

Author

Vasiliya Kril, Michael Hons, Celine Amadori, Claire Zimberger, Laurine Couture, Yara Bouery, Julien Burlaud-Gaillard, Andrei Karpov, Denis Ptchelkine, Alexandra L. Thienel, Beate M. Kümmerer, Ambroise Desfosses, Rhian Jones, Philippe Roingeard, Laurent Meertens, Ali Amara, and Juan Reguera

Subjects
Science
Abstract

Abstract Alphaviruses, such as chikungunya virus (CHIKV), are mosquito-borne viruses that represent a significant threat to human health due to the current context of global warming. Efficient alphavirus infection relies on the activity of the non-structural protein 3 (nsP3), a puzzling multifunctional molecule whose role in infection remains largely unknown. NsP3 is a component of the plasma membrane-bound viral RNA replication complex (vRC) essential for RNA amplification and is also found in large cytoplasmic aggregates of unknown function. Here, we report the cryo-electron microscopy (cryo-EM) structure of the CHIKV nsP3 at 2.35 Å resolution. We show that nsP3 assembles into tubular structures made by a helical arrangement of its alphavirus unique domain (AUD). The nsP3 helical scaffolds are consistent with crown structures found on tomographic reconstructions of the mature viral RCs. In addition, nsP3 helices assemble into cytoplasmic granules organized in a network of tubular structures that contain viral genomic RNA and capsid as well as host factors required for productive infection. Structure-guided mutagenesis identified residues that prevent or disturb nsP3 assemblies, resulting in impaired viral replication or transcription. Altogether, our results reveal an unexpected nsP3-dependent molecular organization essential for different phases of alphavirus infection.

Published
2024
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2. FHL1 is a major host factor for chikungunya virus infection

Author

Cécile Doyen, Thérèse Couderc, Alexis Brugier, R. Juntas-Morales, Philippe Roingeard, Rabah Ben Yaou, Julien Burlaud-Gaillard, Etienne Simon-Loriere, Mohamed Lamine Hafirassou, Sophia Rafasse, Vasiliya Kril, Pierre-Olivier Vidalain, Laura Pezzi, Gisèle Bonne, Lucie Gueneau, Xavier de Lamballerie, Marc Lecuit, Laurent Meertens, Anne Bertrand-Legout, Beate M. Kümmerer, Ali Amara, Lucie Bonnet-Madin, Thibaud Goupil, Constance Delaugerre, Athena Labeau, Monsef Benkirane, Génomes, biologie cellulaire et thérapeutiques (GenCellDi (UMR_S_944)), Collège de France (CdF (institution))-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Biologie des Infections - Biology of Infection, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Virology [Bonn, Germany], University of Bonn Medical Centre, Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses, Institut Pasteur [Paris] (IP), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Equipe Chimie et Biologie, Modélisation et Immunologie pour la Thérapie (CBMIT), Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5), Génomique virale et vaccination, 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), Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Laboratoire de Virologie [CHU Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de maladies infectieuses et tropicales [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Service des Maladies infectieuses et tropicales [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This study received funding from the French Government’s Investissement d’Avenir program, Laboratoire d’Excellence ‘Integrative Biology of Emerging Infectious Diseases’ (ANR-10-LABX-62-IBEID), the ‘Investissements d’Avenir’ program (ANR-10-IHUB-0002, ANR-15-CE15-00029 ZIKAHOST and the INCEPTION program ANR-16-CONV-0005), Institut Pasteur, Inserm and European Research Council. Viruses were provided by the Europe and Virus Archive, which has received funding from the EU Horizon 2020 research and innovation program under grant agreement 653316. The authors thank the EA7310, Laboratoire de Virologie, Université de Corse-Inserm for funding the doctoral position of L.P., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-17-CE15-0029,ZIKAHOST,LES FACTEURS DE L'HÔTE ASSOCIÉS À LA NEUROPATHOGÉNICITÉ DU VIRUS ZIKA(2017), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), Institut National de la Santé et de la Recherche Médicale (INSERM)-Collège de France (CdF (institution))-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris], Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Myologie, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), BUISINE, Soline, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, LES FACTEURS DE L'HÔTE ASSOCIÉS À LA NEUROPATHOGÉNICITÉ DU VIRUS ZIKA - - ZIKAHOST2017 - ANR-17-CE15-0029 - AAPG2017 - VALID, and Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs - - INCEPTION2016 - ANR-16-CONV-0005 - CONV - VALID

Subjects
Male, Permissiveness, viruses, Viral pathogenesis, Muscle Proteins, Host-Derived Cellular Factors, Alphavirus, Viral Nonstructural Proteins, Virus Replication, medicine.disease_cause, Virus, Myoblasts, Mice, 03 medical and health sciences, medicine, Animals, Humans, O'nyong-nyong Virus, Chikungunya, Cells, Cultured, 030304 developmental biology, Host factor, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0303 health sciences, Multidisciplinary, biology, 030306 microbiology, Intracellular Signaling Peptides and Proteins, virus diseases, Fibroblasts, LIM Domain Proteins, biology.organism_classification, Virology, FHL1, 3. Good health, HEK293 Cells, Viral replication, Host-Pathogen Interactions, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Chikungunya Fever, RNA, Viral, Female, Chikungunya virus, Protein Binding
Abstract

Chikungunya virus (CHIKV) is a re-emerging alphavirus that is transmitted to humans by mosquito bites and causes musculoskeletal and joint pain1,2. Despite intensive investigations, the human cellular factors that are critical for CHIKV infection remain unknown, hampering the understanding of viral pathogenesis and the development of anti-CHIKV therapies. Here we identified the four-and-a-half LIM domain protein 1 (FHL1)3 as a host factor that is required for CHIKV permissiveness and pathogenesis in humans and mice. Ablation of FHL1 expression results in the inhibition of infection by several CHIKV strains and o’nyong-nyong virus, but not by other alphaviruses and flaviviruses. Conversely, expression of FHL1 promotes CHIKV infection in cells that do not normally express it. FHL1 interacts directly with the hypervariable domain of the nsP3 protein of CHIKV and is essential for the replication of viral RNA. FHL1 is highly expressed in CHIKV-target cells and is particularly abundant in muscles3,4. Dermal fibroblasts and muscle cells derived from patients with Emery–Dreifuss muscular dystrophy that lack functional FHL15 are resistant to CHIKV infection. Furthermore, CHIKV infection is undetectable in Fhl1-knockout mice. Overall, this study shows that FHL1 is a key factor expressed by the host that enables CHIKV infection and identifies the interaction between nsP3 and FHL1 as a promising target for the development of anti-CHIKV therapies. FHL1 is a key factor expressed by humans and mice that is required for chikungunya virus infection and is therefore a promising target for the development of therapies against chikungunya virus.

Published
2019
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3. New Insights into Chikungunya Virus Infection and Pathogenesis

Author

Laurence Briant, Ali Amara, Olivier Aïqui-Reboul-Paviet, Vasiliya Kril, Génomes, biologie cellulaire et thérapeutiques (GenCellDi (UMR_S_944)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and BRIANT, Laurence

Subjects
Viral pathogenesis, Disease, Alphavirus, Biology, Viral Nonstructural Proteins, medicine.disease_cause, Virus Replication, Antiviral Agents, Virus, Pathogenesis, 03 medical and health sciences, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Virology, medicine, Animals, Humans, Chikungunya, 030304 developmental biology, immune evasion, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, 0303 health sciences, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, musculoskeletal tissues, 030306 microbiology, pathogenesis, nonstructural proteins, Outbreak, virus diseases, biology.organism_classification, 3. Good health, Viral replication, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Chikungunya Fever, Chikungunya virus, host cell interactions
Abstract

International audience; Chikungunya virus (CHIKV) is a re-emerging mosquito-borne alphavirus responsible for major outbreaks of disease since 2004 in the Indian Ocean islands, South east Asia, and the Americas. CHIKV causes debilitating musculoskeletal disorders in humans that are characterized by fever, rash, polyarthralgia, and myalgia. The disease is often self-limiting and nonlethal; however, some patients experience atypical or severe clinical manifestations, as well as a chronic rheumatic syndrome. Unfortunately, no efficient antivirals against CHIKV infection are available so far, highlighting the importance of deepening our knowledge of CHIKV host cell interactions and viral replication strategies. In this review, we discuss recent breakthroughs in the molecular mechanisms that regulate CHIKV infection and lay down the foundations to understand viral pathogenesis. We describe the role of the recently identified host factors co-opted by the virus for infection and pathogenesis, and emphasize the importance of CHIKV nonstructural proteins in both replication complex assembly and host immune response evasion.

Published
2021
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4. FHL1 is a key player of chikungunya virus tropism and pathogenesis

Author

Beate M. Kümmerer, Laura Pezzi, Mohamed Lamine Hafirassou, Lucie Gueneau, Constance Delaugerre, Gisèle Bonne, Thibaud Goupil, Vasiliya Kril, Monsef Benkirane, Julien Burlaud-Gaillard, Lucie Bonnet-Madin, R. Juntas-Morales, Anne Bertrand Legout, Thérèse Couderc, Laurent Meertens, Etienne Simon-Loriere, Philippe Roingeard, Ali Amara, Marc Lecuit, Rabah Ben Yaou, Sophia Rafasse, Alexis Brugier, Xavier de Lamballerie, Pierre-Olivier Vidalain, Cécile Doyen, Athena Labeau, Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Biologie des Infections - Biology of Infection, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Bonn = University of Bonn, Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses, Institut Pasteur [Paris] (IP), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Modélisation et Immunologie pour la Thérapie (CBMIT), Université Paris Descartes - Paris 5 (UPD5), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Service des Maladies infectieuses et tropicales [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Génomes, biologie cellulaire et thérapeutiques (GenCellDi (UMR_S_944)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Bonn, Institut Pasteur [Paris], Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), DIAKITE, andrée, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), and Centre de Recherche en Myologie

Subjects
0106 biological sciences, 0301 basic medicine, viruses, [SDV]Life Sciences [q-bio], Muscle Proteins, Pathogenesis, MESH: Chikungunya Fever, Viral Nonstructural Proteins, Virus Replication, medicine.disease_cause, 01 natural sciences, Mice, Four and a Half LIM domains 1 Tropism, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Animals, Chikungunya, Host factor, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Intracellular Signaling Peptides and Proteins, virus diseases, General Medicine, MESH: Tropism, LIM Domain Proteins, 3. Good health, [SDV] Life Sciences [q-bio], [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Chikungunya virus, MESH: LIM Domain Proteins, Viral protein, Virus infection, Alphavirus, Tropism, Virus, 03 medical and health sciences, MESH: Muscle Proteins, MESH: Intracellular Signaling Peptides and Proteins, medicine, Animals, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, MESH: Mice, Aedes, MESH: Virus Replication, MESH: Chikungunya virus, biology.organism_classification, Virology, 030104 developmental biology, Infectious disease (medical specialty), Chikungunya Fever, MESH: Viral Nonstructural Proteins, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 010606 plant biology & botany
Abstract

Chikungunya is an infectious disease caused by the chikungunya virus (CHIKV), an alphavirus transmitted to humans by Aedes mosquitoes, and for which there is no licensed vaccine nor antiviral treatments. By using a loss-of-function genetic screen, we have recently identified the FHL1 protein as an essential host factor for CHIKV tropism and pathogenesis. FHL1 is highly expressed in muscles cells and fibroblasts, the main CHIKV-target cells. FHL1 interacts with the viral protein nsP3 and plays a critical role in CHIKV genome amplification. Experiments in vivo performed in FHL1-deficient mice have shown that these animals are resistant to infection and do not develop muscular lesions. Altogether these observations, published in the journal Nature [1], show that FHL1 is a key host factor for CHIKV pathogenesis and identify the interaction between FHL1 and nsP3 as a promising target for the development of new antiviral strategies., Le chikungunya est une maladie infectieuse causée par le virus chikungunya (CHIKV), un alphavirus transmis à l’Homme par les moustiques Aedes et contre lequel il n’existe ni vaccin, ni traitements antiviraux. En utilisant une approche de crible génétique par perte de fonction, nous avons récemment identifié la protéine FHL1 comme un facteur cellulaire essentiel pour le tropisme et la pathogénèse du CHIKV. FHL1 est une molécule présente majoritairement dans les cellules musculaires et les fibroblastes, les cibles privilégiées de CHIKV. FHL1 interagit avec la protéine virale nsP3 et joue un rôle décisif dans le mécanisme d’amplification du génome de CHIKV. Des expériences in vivo chez des souris déficientes pour FHL1 ont montré que ces animaux sont résistants à l’infection et ne développent pas de lésions musculaires. L’ensemble de ces observations publiées dans la revue Nature [1] montrent que FHL1 est un facteur cellulaire clé pour la pathogénèse de CHIKV et identifient l’interaction entre FHL1 et nsp3 comme une cible prometteuse pour le développement de nouvelles stratégies antivirales

Published
2020
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