Zika virus induces massive cytoplasmic vacuolization and paraptosis‐like death in infected cells

• Published in: The EMBO journal 2017-06, Vol.36 (12), p.1653-1668
• Main Authors: Monel, Blandine, Compton, Alex A, Bruel, Timothée, Amraoui, Sonia, Burlaud‐Gaillard, Julien, Roy, Nicolas, Guivel‐Benhassine, Florence, Porrot, Françoise, Génin, Pierre, Meertens, Laurent, Sinigaglia, Laura, Jouvenet, Nolwenn, Weil, Robert, Casartelli, Nicoletta, Demangel, Caroline, Simon‐Lorière, Etienne, Moris, Arnaud, Roingeard, Philippe, Amara, Ali, Schwartz, Olivier
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Apoptosis; Astrocytes; Astrocytes - cytology; Astrocytes - physiology; Astrocytes - virology; Caspase; Cell Death; Cells, Cultured; cytopathic effect; Cytopathogenic Effect, Viral; Disease control; EMBO23; Endoplasmic Reticulum; Endoplasmic Reticulum - metabolism; Epithelial Cells; Epithelial Cells - cytology; Epithelial Cells - physiology; Epithelial Cells - virology; Fibroblasts; Fibroblasts - cytology; Fibroblasts - physiology; Fibroblasts - virology; Humans; IFITM; Immunity; Innate immunity; Interferon; Life cycle engineering; Life cycles; Life Sciences; Membrane Proteins; Membrane Proteins - metabolism; Membranes; Microbiology and Parasitology; Mortality; paraptosis; Phosphatidylinositol 3-Kinases; Phosphatidylinositol 3-Kinases - metabolism; Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-akt - metabolism; Replication; RNA-Binding Proteins; RNA-Binding Proteins - metabolism; SEC Translocation Channels; SEC Translocation Channels - metabolism; Signal Transduction; Skin; Translocation; Vacuoles; Vacuoles - metabolism; Vector-borne diseases; Virology; Viruses; ZIKA virus; Zika Virus - pathogenicity
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.15252/embj.201695597

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. Synopsis In human cells, Zika virus (ZIKV) replication occurs in ER‐derived membranes and triggers the formation of large ER‐derived vacuoles leading to “implosive” paraptosis‐like cell death. IFITM3 prevents early stages of ZIKV life cycle. ZIKV induces massive ER‐dependent cytoplasmic vacuolization in human epithelial cells, primary human fibroblasts and human astrocytes. ZIKV induces paraptosis‐like, caspase‐independent cell death. ZIKV‐induced vacuoles are dependent on viral translocation into ER through Sec61 and on PI3K/Akt signaling. Graphical Abstract Characterizing the effects of the antiviral restriction factor IFITM3 shows that viral production can be impeded by counteracting induction of ER stress and cell death.