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Mammarenaviruses depend on endogenous fatty acid synthesis in cell culture systems

ABSTRACT: 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 (r3) LCMV and an r3LCMV variant in which the LCMV glycoprotein complex (GPC) was replaced with that of LASV (r3LCMV LASV) was sensitive to reductions in both exogenously supplied and endogenously synthesized lipids. To explore the relationship between mammarenavirus replication and host lipid metabolism, we performed lipidomic analysis on mock infected and virus-infected VeroS cells. 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. Dependence on FASN activity was also observed for ML29, a Mopeia LASV chimeric virus, as well as the New World mammarenaviruses Tacaribe and Junin Candid #1. Moreover, the FASN dependency was conserved across multiple cell types, including human and murine hepatocellular carcinoma cells (Huh7 and Hepa1 6) and human respiratory epithelial (A549) cells.

INSTRUMENT(S): Synapt XS

ORGANISM(S): Lassa Mammarenavirus (ncbitaxon:11620)

SUBMITTER: Kelly M. Hines Melinda A. Brindley