Modulation of lipid mediator pathways by Staphylococcus aureus in human macrophages

Staphylococcus aureus (S. aureus) causes serious infectious diseases. To develop new treatments against S. aureus infections in-depth knowledge of S. aureus-host interactions is required. The modulation of lipid mediator (LM) pathways by S. aureus remained largely unexplored so far. We show that S. aureus modulates LM formation in a model of osteomyelitis in vivo as well as in osteoclasts and monocyte-derived macrophages (MDM) in vitro. In both murine osteoclasts and human MDM S. aureus exposure caused an elevation of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES-1) expression along with increased prostaglandin E2 formation. In human MDM challenged with S. aureus during polarization, the expression of 15-lipoxygenase (LOX)-1 was prevented, which resulted in impaired formation of 15 LOX-derived LMs. The S. aureus challenge increased the expression of M1 surface markers, while it reduced M2 surface marker expression, indicating that S. aureus shifts M2- towards M1-like MDM. Our results suggest that lipoteichoic acid (LTA) largely accounts for the S. aureus-induced LM pathway modulation. We show that the induction of COX 2 and mPGES 1 expression by LTA is mediated via signaling pathways involving mainly NF κB and p38 MAPK. Impairment of 15-LOX-1 expression by LTA correlates to reduced Lamtor1 expression. We report that S. aureus even alters established phenotypes of fully polarized M1 and M2. Besides, we uncover that the SCV strain JB1 releases less LTA during growth than the wild-type strain 6850, whereas both strains contain comparable amounts of LTA. Our data suggest that COX-derived LMs may promote the survival of S. aureus. Finally, we present that strain JB1 scarcely elicits LM formation in MDM upon short-term exposure. Together, this thesis reveals how LM pathways are modulated by S. aureus. Our data add to the characterization of S. aureus SCVs. Thereby, our findings advance the current knowledge on S. aureus-host interactions.