The role of staphylococcal superantigen-like protein 7 (SSL7) in immune evasion

Abstract

Staphylococcus aureus (S. aureus) is a versatile, opportunistic Gram-positive bacterium associated with the majority of severe hospital or community acquired bacterial infections and a high mortality rate due to increasing antibiotic resistance. S. aureus generates numerous virulence factors that interfere with the host immune defence. Staphylococcal superantigen-like (SSL) proteins comprise a family of virulence factors suspected to target key components of the innate immune system and promote host colonisation and immune evasion. This thesis examined SSL7, a member of the SSL family previously shown to bind to IgA and complement C5, thereby preventing the recognition of IgA by FcαRI and the cleavage of C5, as well as complement-mediated serum hemolytic and bactericidal activity. SSL7 was found to simultaneously confine two molecules of C5 and one molecule of IgA in a large pentameric complex. Steric hindrance of the complex thereby inhibited C5 cleavage and eliminated end-stage complement activation as well as the generation of the anaphylatoxin C5a. Additionally, SSL7 efficiently blocked the formation of C5b- 9 on the surface of Gram-positive bacteria. External SSL7 or SSL7 expressed by the Gram-positive, avirulent Lactococcus lactis enhanced survival of the bacteria in a human whole blood killing assay. Moreover, in an in vitro migration assay and in vivo murine model of peritoneal inflammation, SSL7 inhibited the chemotaxis of inflammatory cells in response to a pathogenic stimulus. Protection against blood killing and reduction of phagocytosis by SSL7 most likely occurs at the level of complement opsonisation, consistent with SSL7’s ability to inhibit the activation of C5, downstream of the main opsonins C3b and C4b. This potentially highlights an exciting new role for C5b or C5b-9 in opsonophagocytosis. With the results included in this study, we can begin to comprehend the specific and efficient interaction of SSL7 with the host immune response and are a step further in the understanding of the complex interactions S. aureus has with its human host. Characterising these interactions could aid in the search for potential targets for novel therapeutic strategies against multi-drug resistant S. aureus.