The type VII secretion system protects Staphylococcus aureus against host-specific fatty acids

The Staphylococcus aureus type VII secretion system (T7SS) exports several proteins that are pivotal for bacterial virulence. The mechanisms underlying T7SS-mediated staphylococcal survival during infection are nevertheless unclear. Here we show that EsxC, a small secreted effector implicated in bacterial persistence, contributes to S. aureus membrane architecture and fluidity. Interestingly, isogenic mutants lacking EsxC, T7SS effectors (EsxA or EsxB), and the membrane-bound EssC are more sensitive to killing by the host-specific fatty acid, linoleic acid (LA), compared to the wild-type. We demonstrate that LA induces more cell membrane damage in the T7SS mutants, although they do not bind differentially to LA. Membrane lipid profiles show that T7SS mutants are also less able to incorporate LA into their membrane phospholipids. Proteomics analyses of wild-type and mutant cell fractions reveal that, in addition to compromising membranes, T7SS defects readily induce bacterial stress and hamper their response to LA challenge. Together, our findings indicate that T7SS is crucial for S. aureus membrane integrity and homeostasis, which is critical when bacteria encounter antimicrobial fatty acids.