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

SIMPLE SUMMARY: Zika virus (ZIKV) is a mosquito-borne virus first isolated from the Zika forest, Uganda, in 1947, which has been spreading across continents since then. We now know ZIKV causes both microencephaly in newborns and neurological complications in adults; however, no effective treatment options have yet been found. A more complete understanding of Zika-infection-mediated pathogenesis and host responses is required to enable the development of novel treatment strategies. In this study, efforts were made to elucidate the host responses following Zika virus infection using several astrocyte cell models, as astrocytes are a major cell type within the central nervous system (CNS) with significant antiviral ability. Our data suggest that astrocytes can resist ZIKV both in an interferon type I- and III-independent manner and suggest that an early and more diverse antiviral response may be more effective in controlling Zika infection. This study also identifies astrocyte cellular models that appear to display differential abilities in the control of viral infection, which may assist in the study of alternate neurotropic virus infections. Overall, this work adds to the growing body of knowledge surrounding ZIKV-mediated cellular host interactions and will contribute to a better understanding of ZIKV-mediated pathogenesis. 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.