A bacterial fatty acid enzyme hijacks nucleic acid-sensing Toll-like receptor signaling.

Innate immune recognition shapes infection outcomes by linking microbial detection to host defense. Although pattern recognition receptors are classified by the ligands they detect (lipids, peptidoglycans, or nucleic acids) cross-talk between these pathways is increasingly recognized. Staphylococcus aureus, a major cause of skin and soft tissue infections, can persist intracellularly, evading immunity and antibiotics. Here, we describe a lipid-based immune evasion strategy in which the S. aureus enzyme oleate hydratase (OhyA) converts host fatty acids into hydroxylated lipids that antagonize TLR3-TRIF-IRF7 signaling, a pathway activated by double-stranded RNA. Deletion of ohyA unleashed this pathway, triggering rapid bacterial clearance, whereas loss of TLR3, TRIF, or IRF7 restored bacterial persistence, establishing a noncanonical antibacterial role for an antiviral signaling pathway. These findings identify a previously unrecognized interface between bacterial lipid metabolism and antiviral immune machinery, highlighting how pathogens manipulate cross-kingdom signaling to evade intracellular immunity.