Staphylococcus aureus is a serious human pathogen. It causes higher rates of disease in New Zealand than other developed countries and is a major cause of skin and soft tissue infections, bacteraemia, and endocarditis. Its success as a pathogen can be attributed to the large number of diverse virulence factors it produces that allow it to invade its host and then evade the host immune defences. A family of fourteen secreted molecules named the Staphylococcal Superantigen-like (SSL) proteins are important virulence factors that are responsible for immune evasion by S. aureus. By binding to constituents of the immune system including complement components, immunoglobulin, and cell surface receptors, they block essential anti-staphylococcal immune functions.
Staphylococcal superantigen-like protein 10 (SSL10) is an IgG1-binding protein of S. aureus that targets multiple host defences including C1q-mediated complement activity, coagulation, FcγR binding and CXCR4-mediated leukocyte migration. We have solved the crystal structure of SSL10 and reveal the IgG1-binding interface that includes residues Phenylalanine 166 (F166), Asparagine 168 (N168) and Tyrosine 179 (Y179). This site is structurally conserved across all the crystalized SSL proteins and directly overlaps with the sialyl Lewis X binding site on the glycan-binding proteins SSL4, SSL5, and SSL11. The combined SSL10-FNY IgG1-binding mutant lacks the ability to prevent FcγR binding to IgG and C1q-mediated classical complement activity. However total end-point complement (MAC formation) is only partially restored. Thus, we reveal an IgG-independent role of SSL10 in complement inhibition that targets the classical and lectin complement pathways after C3 cleavage but prior to C5 cleavage. Surprisingly SSL10-FNY displays an enhanced inhibition of both complement and coagulation. This study highlights a diversion to the predominant functional role of SSL10 in an immunological environment lacking IgG1.