Zika virus induces massive cytoplasmic vacuolization and paraptosis‐like death in infected cells |
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Authors: | Alex A Compton Timothée Bruel Sonia Amraoui Julien Burlaud‐Gaillard Nicolas Roy Florence Guivel‐Benhassine Françoise Porrot Pierre Génin Laurent Meertens Laura Sinigaglia Nolwenn Jouvenet Robert Weil Nicoletta Casartelli Caroline Demangel Etienne Simon‐Lorière Arnaud Moris Philippe Roingeard Ali Amara Olivier Schwartz |
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Institution: | 1. Virus & Immunity Unit, Institut Pasteur, Paris, FranceThese authors contributed equally to this work;2. Virus & Immunity Unit, Institut Pasteur, Paris, France;3. INSERM U966 & Platefome IBiSA de Microscopie Electronique, Université Fran?ois Rabelais and CHRU de Tours, Paris, France;4. Signaling and Pathogenesis Laboratory and CNRS UMR3691, Institut Pasteur, Paris, France;5. INSERM U944, CNRS 7212 Laboratoire de Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie, H?pital Saint‐Louis, Paris, France;6. Viral Genomics and Vaccination Unit, Institut Pasteur, Paris, France;7. UMR CNRS 3569, Paris, France;8. Immunobiology of Infection Unit, Institut Pasteur, Paris, France;9. Institut Pasteur, Unité de Génétique Fonctionnelle des Maladies Infectieuses, Paris, France;10. CNRS URA 3012, Paris, France;11. Sorbonne Universités, UPMC Univ Paris 06, INSERM U1135, CNRS ERL 8255, Center for Immunology and Microbial Infections – CIMI‐Paris, Paris, France |
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Abstract: | The cytopathic effects of Zika virus (ZIKV) are poorly characterized. Innate immunity controls ZIKV infection and disease in most infected patients through mechanisms that remain to be understood. Here, we studied the morphological cellular changes induced by ZIKV and addressed the role of interferon‐induced transmembrane proteins (IFITM), a family of broad‐spectrum antiviral factors, during viral replication. We report that ZIKV induces massive vacuolization followed by “implosive” cell death in human epithelial cells, primary skin fibroblasts and astrocytes, a phenomenon which is exacerbated when IFITM3 levels are low. It is reminiscent of paraptosis, a caspase‐independent, non‐apoptotic form of cell death associated with the formation of large cytoplasmic vacuoles. We further show that ZIKV‐induced vacuoles are derived from the endoplasmic reticulum (ER) and dependent on the PI3K/Akt signaling axis. Inhibiting the Sec61 ER translocon in ZIKV‐infected cells blocked vacuole formation and viral production. Our results provide mechanistic insight behind the ZIKV‐induced cytopathic effect and indicate that IFITM3, by acting as a gatekeeper for incoming virus, restricts virus takeover of the ER and subsequent cell death. |
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Keywords: | cell death cytopathic effect
IFITM
paraptosis ZIKA virus |
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