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DOE OSTI · 1688419

A global lipid map defines a network essential for Zika virus replication

Leier, Hans C.·Weinstein, Jules B.·Kyle, Jennifer E.·Lee, Joon-Yong·Bramer, Lisa M.·Stratton, Kelly G.·Kempthorne, Douglas·Navratil, Aaron R.·Tafesse, Endale G.·Hornemann, Thorsten·Messer, William B.·Dennis, Edward A.·Metz, Thomas O.·Barklis, Eric·Tafesse, Fikadu G.
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Abstract

Zika virus (ZIKV), an emerging mosquito-borne pathogen of global concern, remodels intra-cellular lipid membranes to form replication factories. How ZIKV regulates lipid networks to allow infection, and consequences for disease is poorly understood. Here, we performed comprehensive lipidomics to create a lipid network map during ZIKV infection. We found that ZIKV significantly alters host lipid composition with striking changes seen within sub-classes of sphingolipids. We also demonstrated that ectopic expression of NS4B, one of the non-structural proteins of ZIKV with known roles in ZIKV replication resulted in similar changes on cellular lipidome. Ceramide, a key bioactive molecule with functions in signaling and apoptosis, redistributes to ZIKV replication factories. Increase of ceramide through knockout of sphingomyelin synthase or via sphingomyelinase-catalyzed degradation of sphingomyelin to ceramide sensitizes cells to ZIKV infection. Remarkably, we observed an enrichment of pro-apoptotic ceramide sub-species in infected cells, providing a link between ZIKV biogenesis and apoptosis. 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.

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60 APPLIED LIFE SCIENCESlipidomicsmetabolomicssphingolipidsvirus–host interactions

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Leier, Hans C., Weinstein, Jules B., Kyle, Jennifer E., Lee, Joon-Yong, Bramer, Lisa M., Stratton, Kelly G., Kempthorne, Douglas, Navratil, Aaron R., Tafesse, Endale G., Hornemann, Thorsten, Messer, William B., Dennis, Edward A., Metz, Thomas O., Barklis, Eric, Tafesse, Fikadu G.. 2020-07-21. A global lipid map defines a network essential for Zika virus replication. https://doi.org/10.1038/s41467-020-17433-9

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