Abstract
Zika virus (ZIKV), an arbovirus of global concern, remodels intracellular membranes to form replication sites. How ZIKV dysregulates lipid networks to allow this, and consequences for disease, is poorly understood. Here, we perform comprehensive lipidomics to create a lipid network map during ZIKV infection. We find that ZIKV significantly alters host lipid composition, with the most striking changes seen within subclasses of sphingolipids. Ectopic expression of ZIKV NS4B protein results in similar changes, demonstrating a role for NS4B in modulating sphingolipid pathways. Disruption of sphingolipid biosynthesis in various cell types, including human neural progenitor cells, blocks ZIKV infection. Additionally, the sphingolipid ceramide redistributes to ZIKV replication sites, and increasing ceramide levels by multiple pathways sensitizes cells to ZIKV infection. Thus, we identify a sphingolipid metabolic network with a critical role in ZIKV replication and show that ceramide flux is a key mediator of ZIKV infection.
Highlights
Zika virus (ZIKV), an arbovirus of global concern, remodels intracellular membranes to form replication sites
To understand how cellular lipid metabolism is altered by ZIKV infection, we carried out a global lipidomic survey of the model Huh[7] human hepatic carcinoma cell line[20] infected for 24 or 48 h with Asian lineage ZIKV strain FSS13025 (Fig. 1a)
Principal component analysis (PCA) of these observations confirmed that infection status and timepoint (24 or 48 hpi) accounted for most of these changes, with changes in lipid composition between mock and infected cells increasing over time (Fig. 1b)
Summary
Zika virus (ZIKV), an arbovirus of global concern, remodels intracellular membranes to form replication sites. ZIKV carries out each stage of its replication cycle in close association with cellular membranes, including the synthesis of new genome copies and assembly of viral particles within specialized replication complexes (RCs) formed from extensively remodeled ER membranes[13] These steps appear to require a specific lipid milieu, as flaviviruses presumably modify various host lipid pathways to create this milieu[14,15,16]. To systematically map the host lipid–virus interaction networks in an unbiased manner, we have carried out a global lipidomic survey in human cells infected with ZIKV or ectopically expressing NS4B, one of the nonstructural proteins of ZIKV known to be involved in forming viral replication sites[19]. Genetic knockout of sphingomyelin synthesis drastically increases cellular permissiveness to ZIKV, indicating that ceramide or its derivatives, rather than sphingomyelin, are required for ZIKV infection
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