PNNL

Abstract

Zika virus (ZIKV) is a positive-sense RNA virus that remodels host membrane to establish sites of replication and assembly. To determine how ZIKV modulates the host lipid repertoire in an unbiased manner, we performed comprehensive lipid profiling of human cells infected with ZIKV. We found that ZIKV replication triggers significant changes in the cellular sphingolipidomes especially that of ceramide which highly enriched during infection. Disruption of sphingolipid biosynthesis with CRISPR/Cas9 gene-editing or small molecule inhibitors effectively blocks ZIKV replication. Sphingomyelin redistributes to ZIKV replication sites, and the sphingomyelinase-catalyzed degradation of sphingomyelin to ceramide is the critical pathway to establish infection effectively. Inhibition of sphingomyelinase attenuated ZIKV replication, while the accumulation of intracellular ceramide through knockout of sphingomyelin synthesis enhanced ZIKV infection. Thus, we identify a sphingolipid salvage pathway with a critical role in ZIKV replication and show that ceramide is a key mediator of ZIKV pathogenesis.