Faculty Bibliography

The generation of oxidative stress is a host strategy used to control Staphylococcus aureus infections. Sulfur containing amino acids, cysteine and methionine, are particularly susceptible to oxidation because of the inherent reactivity of sulfur. Due to the constant threat of protein oxidation, many systems evolved to protect S. aureus from protein oxidation or to repair protein oxidation after it occurs. The S. aureus peptide methionine sulfoxide reductase (Msr) system reduces methionine sulfoxide to methionine. Staphylococci have four Msr enzymes, which all perform this reaction. Deleting all four msr genes in USA300 LAC (Δmsr) sensitizes S. aureus to hypochlorous acid (HOCl) killing, however, Δmsr does not exhibit increased sensitivity to H₂O₂ stress or superoxide anion stress generated by paraquat or pyocyanin. Consistent with increased susceptibility to HOCl killing, Δmsr is slower to recover following co-culture with both murine and human neutrophils than USA300 wildtype. Δmsr is attenuated for dissemination to the spleen following murine intraperitoneal infection and exhibits reduced bacterial burdens in a murine skin infection model. Notably, no differences in bacterial burdens were observed in any organ following murine intravenous infection. Consistent with these observations, USA300 wildtype and Δmsr have similar survival phenotypes when incubated with murine whole blood. However, Δmsr is killed more efficiently by human whole blood. These findings indicate that species-specific immune cell composition of the blood may influence the importance of Msr enzymes during S. aureus infection of the human host.IMPORTANCEOxidative stress is a host defense strategy to control bacterial infections, and bacteria have evolved systems to counteract this innate immune defense. Here we investigate the peptide methionine sulfoxide reductase system in Staphylococcus aureus that repairs oxidized methionine residues in proteins, preventing the need to resynthesize damaged proteins de novo Most organisms have an Msr system, and in S. aureus these enzymes are protective against HOCl killing, the major oxidant produced by neutrophils. The S. aureus Msr system does not have a significant contribution to pathogenesis in bacteremia murine infection models but does protect S. aureus in both skin and intraperitoneal infection models. Strains lacking Msr activity are killed equivalently to wildtype by murine whole blood, and Δmsr is more sensitive to killing by human whole blood than the wildtype strain. These data identify the Msr enzymes as important and potentially specific factors for S. aureus pathogenesis in the human host.