Mammarenaviruses depend on endogenous fatty acid synthesis in cell culture systems

Lassa virus (LASV) and lymphocytic choriomeningitis virus (LCMV) are Old World mammarenaviruses that, like all viruses, rely on host-derived biological molecules to complete their replication cycle. Identifying host factors essential for mammarenavirus replication may reveal novel targets for antiviral intervention. To this end, we found that replication of recombinant tri-segmented r3LCMV and r3LCMV LASV chimera (r3LCMV-LASV) was sensitive to reductions in both exogenously supplied and endogenously synthesized lipids. Lipidomic analysis on mock-infected and virus-infected VeroS cells revealed infection with r3LCMV-LASV increased the abundance of triacylglycerols (TG), phosphatidylcholine (PC), and phosphatidylglycerol (PG), while decreasing levels of ceramides, phosphatidylethanolamine (PE), and phosphatidylserine (PS). Although TG levels rose during infection, pharmacologic inhibition of TG synthesis did not impair viral replication. In contrast, inhibition of fatty acid synthase (FASN), a key enzyme upstream of TG synthesis, significantly reduced r3LCMV-LASV and r3LCMV spread. FASN inhibition suppressed both viral genome replication and viral budding. The addition of oleic acid, but not palmitic acid (the principal product of FASN), rescued the inhibitory effect of FASN blockade. Reducing FASN using shRNA conferred similar effects. Dependence on FASN activity was observed across multiple New and Old World mammarenaviruses and in multiple different cell lines, further reinforcing the importance of fatty acid synthase for productive mammarenaviral infection.