Transcriptional signatures of Zika virus infection in astrocytes

Blake Schouest,Dawn M Szeltner,Erik K Flemington,Elizabeth A Scheef,Nicholas J Maness,Andrew G Maclean,Melody Baddoo,Nathan Ungerleider,Tiffany A Peterson

doi:10.1007/s13365-020-00931-3

Abstract

Astrocytes are an early and important target of Zika virus (ZIKV) infection in the developing brain, but the impacts of infection on astrocyte function remain controversial. Given that nonhuman primate (NHP) models of ZIKV infection replicate aspects of neurologic disease seen in human infections, we cultured primary astrocytes from the brain tissue of infant rhesus macaques and then infected the cells with Asian or African lineage ZIKV to identify transcriptional patterns associated with infection in these cells. The African lineage virus appeared to have greater infectivity and promote stronger antiviral signaling, but infection by either strain ultimately produced typical virus response patterns. Both viruses induced hypoxic stress, but the Asian lineage strain additionally had an effect on metabolic and lipid biosynthesis pathways. Together, these findings describe an NHP astrocyte model that may be used to assess transcriptional signatures following ZIKV infection.

Highlights

For decades following the initial isolation of Zika virus (ZIKV) from a sentinel rhesus macaque in Uganda in 1947 (Dick et al 1952), ZIKV was not considered a significant human pathogen (Gubler et al 2017)
Twenty-four hours following infection with either Asian (Rio-U1) or African (MR766) lineage ZIKV, cultured astrocytes (GFAP+) from infant macaques were co-positive for the viral antigens envelope (E) and nonstructural protein 3 (NS3), indicating permissiveness to infection (Figs. 1a–e and S1a-e)
A higher proportion of cells infected with MR766 stained positively for viral antigens compared with glial fibrillary acidic protein (GFAP), cultured astrocytes have lower GFAP expression than in vivo, possibly accounting for this effect

Summary

Introduction

For decades following the initial isolation of Zika virus (ZIKV) from a sentinel rhesus macaque in Uganda in 1947 (Dick et al 1952), ZIKV was not considered a significant human pathogen (Gubler et al 2017). The Pacific island outbreaks in 2007 and 2013 changed the perception that ZIKV could not cause widespread outbreaks or significant human disease (Musso and Gubler 2016), outcomes which are well recognized following the recent epidemics. Despite these epidemiological patterns, analyses comparing Asian lineage viruses, which are responsible for modern outbreaks, with ancestral African lineage viruses have paradoxically found higher virulence in African isolates (Simonin et al 2017). Given that astrocytes are an early and important target of ZIKV in the developing brain (Potokar et al 2019; van den Pol et al 2017), we hypothesized that astrocytes from infant macaques would be susceptible to ZIKV infection and that these cells may be amenable to an in vitro culture system that could be used to explore transcriptional signatures associated with ZIKV infection

Methods

Results

Conclusion