PNNL

Abstract

A comprehensive understanding of host dependency factors for SARS-CoV-2 remains elusive. We mapped lipid metabolic pathways that are altered during infection of human cells with SARS-CoV-2 using nontargeted lipidomics. We found changes in 514 individual lipid species, especially in the glycerolipid family. We further correlated these changes with specific viral protein activity by individually transfecting human cells with each viral protein and analyzing the resulting lipid profiles. We showed that lipid droplets, as neutral glycerolipid reservoirs, increase in size and number during infection. Finally, we used small-molecule gycerolipid biosynthesis inhibitors, including the FDA-approved drug orlistat, to demonstrate that SARS-CoV-2 depends upon host lipid biosynthesis to produce infectious virions. We found that this inhibition was effective against all four variants of concern (alpha, beta, gamma, and delta), demonstrating the conservation of glycerolipid biosynthesis as a host dependency factor that supports this evolving virus.