Lysophosphatidic acid promotes lipid metabolism through AMPK signaling to support Coxsackievirus infection

Lysophosphatidic acid (LPA) is a bioactive signaling lipid that regulates cellular processes, including growth, survival, differentiation, and metabolic homeostasis. LPA signals through its G-protein-coupled receptor, LPA receptor 1 (LPAR1), to modulate pathways controlling cellular signaling and metabolism. Viruses rely on cellular metabolism for efficient replication, and lipids function at nearly every stage in virus replication. Using Coxsackievirus B3 (CVB3) as a model, we performed global metabolomic analysis of infected Huh7 cells and identified lipid classes altered upon infection. Using small-molecule inhibitors targeting lipids, we identified LPA signaling as a key factor in CVB3 infection. Inhibiting LPA signaling with AM095 or via siRNA knockdown reduces CVB3 infection by over 100-fold. We find that LPA mediates CVB3 genome replication. Mechanistically, LPA signaling through LPAR1 facilitates cellular lipid synthesis by regulating AMPK and downstream enzymes, including fatty acid synthase (FASN) and acetyl-CoA carboxylase 1 (ACC1). In AM095-treated cells, lipid droplets are depleted, and cells exhibit a quiescent-like phenotype. Replenishing lipids fully rescues viral replication, indicating that LPA's proviral function is to facilitate lipid synthesis through AMPK signaling. These findings identify LPA-LPAR1 signaling as a regulator of host lipid metabolism that supports CVB3 replication, revealing a metabolic axis for antiviral intervention.IMPORTANCECellular metabolism supports virus infection by providing energy and the building blocks for virus replication. During viral infection, cellular metabolism changes drastically, and we find that lipids are among the most significantly changed metabolites during infection with Coxsackievirus B3, a picornavirus. We used metabolomics to characterize changes in metabolites in infected cells, and we followed up on these data with a drug screen with molecules targeting cellular lipid pathways. We identified lysophosphatidic acid (LPA) signaling as a major regulator of Coxsackievirus infection, supporting viral genome replication via lipid synthesis. This study underscores the importance of lipids in viral infection, uncovers new mechanisms by which LPA signals, and provides new insight into LPA's function in Coxsackievirus infection.