Abstract 1421 Staphylococcus aureus oleate hydratase produces ligands that activate PPARalpha

Commensal gut bacteria use oleate hydratase (OhyA) to release a spectrum of hydroxylated fatty acids using host-derived unsaturated fatty acids. These compounds are thought to attenuate the immune response, but the underlying signaling mechanism(s) remain to be established. The pathogen Staphylococcus aureus also expresses an OhyA and 10-hydroxyoctadecanoic acid (h18:0) is the most abundant OhyA metabolite found at Staphylococcal skin infection sites. Here, we show h18:0 stimulates the transcription of a set of lipid metabolism genes associated with the activation of peroxisome proliferator activated receptor (PPAR) in the RAW 264.7 macrophage cell line and mouse primary bone marrow-derived macrophages (BMDM). Cell-based transcriptional reporter assays show h18:0 selectively activates PPARα. Radiolabeling experiments with BMDM show [1-14C]h18:0 is not incorporated into cellular lipids, but is degraded by β-oxidation, and mass spectrometry detected shortened fragments of h18:0 released into the media. The catabolism of h18:0 was >10-fold lower in BMDM isolated from Ppara-/- knockout mice, and we recover 1-log fewer S. aureus cells from the skin infection site of Ppara-/- knockout mice compared to wildtype mice. These data identify PPARα as a target for OhyA-derived hydroxy fatty acids and support the existence of an OhyA-PPARα signaling axis that functions to suppress the innate immune response to S. aureus. This work was supported by National Institutes of Health, United States grants R00-AI166116 (C. D. R.) and R01-GM034496 (C. O. R.), and the American Lebanese Syrian Associated Charities, United States. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.