Identification of signaling pathways that respond to h18:0 in macrophages
Commensal gut bacteria produce oleate hydratase (OhyA) to hydroxylate host unsaturated fatty acids that are then released from the cells. Staphylococcus aureus is a major pathogen that also expresses OhyA to produce primarily 10-hydroxyoctadecanoic acid at the infection site. S. aureus strains lacking the ohyA gene have compromised virulence in soft tissue and endocarditis infection models. OhyA products are implicated in suppressing the innate immune response, but the mechanisms are not clearly defined. The discovery that 10-hydroxyoctadecanoic acid potently activates peroxisome proliferator activated receptor alpha (PPARalpha) links bacterial unsaturated fatty acid hydroxylation to the initiation of a specific mammalian signal transduction pathway. PPARalpha activation is known to suppress the innate immune response, in addition to up-regulating fatty acid oxidation, which functions to inactivate the signal. Thus, S. aureus utilizes an OhyA-PPARalpha signaling axis to attenuate the innate immune response and promote pathogenesis.