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

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.

Transcriptional Changes during Naturally Acquired Zika Virus Infection Render Dendritic Cells Highly Conducive to Viral Replication

“…The reasons for this discrepancy are not clear at present but may relate to altered gene expression kinetics of these two transcripts during naturally-acquired infection. In addition, previous studies have shown that IFITM1 is expressed on the plasma membrane and the early endosomes while IFITM3 can be preferentially detected in late endosomes(Bailey et al, 2014; Gorman et al, 2016; Monel et al, 2017; Savidis et al, 2016b). Nevertheless, there is evidence that ZIKV can antagonize interferon-signaling pathways by targeting key proteins involved in signaling downstream of the IFN receptor.…”

The A–Z of Zika drug discovery

“…They therefore tested the activity of several kinase inhibitors and verified that they could prevent the onset of vacuoles, particularly the specific class-1 PI3K (ZSTK474) and AKT (triciribine) inhibitors. However, none of the tested inhibitors blocked ZIKV infection [144].…”

“…Monel et al described in-depth the vacuolization of ZIKVinfected cells and suggested that they undergo a paraptosis-like death [144], which is associated with the activity of phophoinositide 3-kinase (PI3K) [145] and membrane-associated protein kinase (MAPK) [146]. They therefore tested the activity of several kinase inhibitors and verified that they could prevent the onset of vacuoles, particularly the specific class-1 PI3K (ZSTK474) and AKT (triciribine) inhibitors.…”

Construction, expression and antiviral activity analysis of recombinant adenovirus expressing human IFITM3 in vitro

“…Among ISGs, IFITM3 is one of the most promising antiviral agents with better application prospect [18,35]. Firstly, IFITM3 has a broad-spectrum antiviral activity, which have been reported to inhibit entering of N20 kinds of viruses, including different subtypes of influenza virus, severe acute respiratory syndrome (SARS) coronavirus, human immunodeficiency virus (HIV), Ebola virus, dengue, and West Nile viruses and so on [26][27][28][29][30][35][36][37]. Secondly, to date, IFITM3 is the only ISG discovered displaying a bona fide role in blocking virus entry, to defense virus outside the cell.…”

“…Amino-terminal mutants of primate IFITM3 are more easily incorporated into HIV virions, resulting in enhanced inhibition of HIV-1 fusion [25]. Among the IFITMs, IFITM3 was widely studied for its wide range of effective antiviral activities, which could restrict Dengue virus, SARS coronavirus, Ebola virus, HCV, influenza A virus, Zika virus, West Nile virus, and so on [26][27][28][29][30]. We also discovered that overexpression of human IFITM3 significantly restricted vaccinia virus infection, replication and proliferation, mainly by interfering with virus entry in a low pH-dependent manner [18].…”