Astrocyte Control of Zika Infection Is Independent of Interferon Type I and Type III Expression

Abstract

Zika virus (ZIKV) is a pathogenic neurotropic virus that infects the central nervous system (CNS) and results in various neurological complications. Astrocytes are the dominant CNS cell producer of the antiviral cytokine IFN-β, however little is known about the factors involved in their ability to mediate viral infection control. Recent studies have displayed differential responses in astrocytes to ZIKV infection, and this study sought to elucidate astrocyte cell-specific responses to ZIKV using a variety of cell models infected with either the African (MR766) or Asian (PRVABC59) ZIKV strains. Expression levels of pro-inflammatory (TNF-α and IL-1β) and inflammatory (IL-8) cytokines following viral infection were low and mostly comparable within the ZIKV-resistant and ZIKV-susceptible astrocyte models, with better control of proinflammatory cytokines displayed in resistant astrocyte cells, synchronising with the viral infection level at specific timepoints. Astrocyte cell lines displaying ZIKV-resistance also demonstrated early upregulation of multiple antiviral genes compared with susceptible astrocytes. Interestingly, pre-stimulation of ZIKV-susceptible astrocytes with either poly(I:C) or poly(dA:dT) showed efficient protection against ZIKV compared with pre-stimulation with either recombinant IFN-β or IFN-λ, perhaps indicating that a more diverse antiviral gene expression is necessary for astrocyte control of ZIKV, and this is driven in part through interferon-independent mechanisms.

Transcriptomic reveals the ferroptosis features of host response in a mouse model of Zika virus infection

“…ZIKV is a pathogenic neurotropic virus that crosses the blood‐brain barrier, infects the CNS of adults, and causes various neurological complications 34 . ZIKV has been detected in the brains and CSF of adults 10,35 .…”

“…ZIKV is a pathogenic neurotropic virus that crosses the bloodbrain barrier, infects the CNS of adults, and causes various neurological complications. 34 ZIKV has been detected in the brains and CSF of adults. 10,35 In adult mice, ZIKV preferentially targets memory-related brain regions, inhibits hippocampal long-term potentiation, and induces memory impairment.…”

HLA-A, HSPA5, IGFBP5 and PSMA2 Are Restriction Factors for Zika Virus Growth in Astrocytic Cells

“…Among the ZIKV dysregulated cellular functions at 48 h post ZIKV infection, which was the timepoint with the largest number of dysregulated proteins, MAPK1 was predicted to be activated and STAT1/2 inhibited ( Figure 1 ). MAPK1 dysregulation induces chorio-retinal atrophy and optic nerve abnormalities in ZIKV infections and STAT1/2 is involved in antiviral responses; in addition, ZIKV NS5 protein-mediated STAT2 degradation modulates type I and III interferon responses [ 51 , 67 , 68 , 69 ]. Other molecules dysregulated by ZIKV among the top ZIKV dysregulated functions at 48 hpi included over-expressed proteins such as STAT1, IFIT2/3 and HLA-A and under-expressed proteins such as LAMP2 ( Figure 3 ).…”

“…LC-MS/MS studies in human fetal neural progenitor cells and on astrocytic cells, respectively, identified dysregulations in cell proliferation, differentiation and migration and neural cell adhesion molecule (NCAM1) as a receptor for ZIKV infection [ 26 , 49 , 50 ]. iPSC-derived astrocytic cells were also studied and linked ZIKV infection to DNA breakage and reactive oxygen species imbalance in the cells [ 51 , 52 ]. RNA approaches to understanding ZIKV infection have also yielded promising results.…”

Expression and mechanisms of interferon-stimulated genes in viral infection of the central nervous system (CNS) and neurological diseases

“…Another study showed that rapid type I IFN response protected astrocytes from virus-induced cytopathic effects upon infection with flavivirus, tick-borne encephalitis virus (TBEV), JEV, WNV, and Zika virus (ZIKV), thus limiting the spread of these viruses ( 119 ). In addition, type I and type III IFN-independent antiviral pathways were found to be involved in the control of astrocytes during ZIKV infection ( 120 ). In summary, the intrinsic structural antiviral response of astrocytes combined with rapid induction of type I IFNs is instrumental in protecting astrocytes and inhibiting viral replication in the CNS ( 121 ).…”