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Updated: Mar 3, 2026
Zika Virus Infectious Cell Culture System and the In Vitro Prophylactic Effect of Interferons
Published on: August 23, 2016
Zika virus induces massive cytoplasmic vacuolization and paraptosis-like death in infected cells
Blandine Monel1, Alex A Compton2, Timothée Bruel1
1Virus & Immunity Unit, Institut Pasteur, Paris, France.
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.
Insights
Zika virus (ZIKV) causes cell death through massive vacuolization. Interferon-induced transmembrane protein 3 (IFITM3) restricts ZIKV replication and protects cells from this ER-derived cell death.
Area of Science:
- Virology
- Cell Biology
- Immunology
Background:
- Zika virus (ZIKV) cytopathic effects and innate immune control mechanisms are not fully understood.
- Interferon-induced transmembrane proteins (IFITM) are known broad-spectrum antiviral factors.
Purpose of the Study:
- To investigate ZIKV-induced cellular morphological changes.
- To determine the role of IFITM proteins in ZIKV replication and pathogenesis.
Main Methods:
- Studied ZIKV-induced cytopathic effects in human epithelial cells, fibroblasts, and astrocytes.
- Assessed the impact of IFITM3 levels on ZIKV infection.
- Investigated the origin and signaling pathways of ZIKV-induced vacuoles.
- Utilized Sec61 ER translocon inhibition to assess its effect on vacuole formation and viral production.
Main Results:
- ZIKV infection leads to massive vacuolization and implosive cell death, a form of paraptosis.
- Reduced IFITM3 levels exacerbate ZIKV-induced cell death.
- Vacuoles originate from the endoplasmic reticulum (ER) and depend on the PI3K/Akt pathway.
- Inhibiting the Sec61 ER translocon blocks vacuole formation and ZIKV production.
Conclusions:
- ZIKV induces a unique caspase-independent cell death pathway involving ER-derived vacuoles.
- IFITM3 acts as a gatekeeper, limiting ER hijacking by ZIKV and subsequent cell death.
- Understanding these mechanisms provides insight into ZIKV pathogenesis and potential therapeutic targets.
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