SSLs immune manipulation in S aureus colonization, infection, and a potential therapy against pneumonia

PROJECT SUMMARY / ABSTRACT Staphylococcus aureus associated pneumonia accounts for an estimated 50,000 staphylococcal infections annually in the United States. S. aureus is one of the leading etiologic agents of ventilator-associated pneumonia in the intensive care environment. S. aureus pneumonia has a high rate of mortality due to the prevalence of antibiotic resistance and lack of an effective vaccine. Although S. aureus colonization (30% of humans) is strongly associated with higher risks for clinical infections, most colonized individuals will not experience S. aureus infections, suggesting that S. aureus maintains a dedicated balance with the host. Our knowledge gaps between S. aureus colonization and infections might explain the lack of a vaccine. Neutrophils are the first host defense against S. aureus. During pulmonary infection, the neutrophil influx is a double-edged sword: neutrophils clear the invading pathogens, but overzealous neutrophils can cause tissue damage, leading to pneumonia. Hence, understanding the mechanisms by which S. aureus inhibits neutrophil migration is crucial to decipher how S. aureus maintains a delicate balance with the host. The S. aureus Superantigen-Like protein (SSL) family is an example of a complex immune evasion system of S. aureus. Despite their structural similarity to superantigens (SAgs), SSLs display a wide range of immune inhibition activities, in contrast to SAgs’ massive immune activation. Recently, we showed that SSL11 mediates motility arrest in human neutrophils by inducing cell adhesion. In the current study, we propose to study the mechanisms of SSL11 neutrophil inhibiting (Aim 1) and the roles of SSLs in S. aureus colonization and infection (Aim 2) and to test whether SSL11 inhibits pneumonia via inhibiting neutrophil infiltration in a mouse model (Aim 3). This proposal will characterize a previously underappreciated mechanism of bacterial toxin action to evade neutrophil function, provide insight into how S. aureus establishes and maintains a balance with the host immune system for colonization and infection, and reveal a potential new therapy to treat pneumonia associated with massive neutrophil migration.