How S. aureus protein SSL11 inhibits neutrophil migration

SUMMARY S. aureus-associated pneumonia accounts for an estimated 50,000 staphylococcal infections per year 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 the lack of an effective vaccine. During pulmonary infection, neutrophil influx is a double-edged sword: neutrophils clear the invading pathogens, or overzealous neutrophils may cause tissue damage leading to pneumonia. Hence, understanding the mechanisms by which S. aureus keeps lung neutrophils at rest is crucial to decipher how S. aureus maintains its silent colonization state and when/how its presence becomes pathogenic. The Staphylococcal Superantigen-Like protein (SSL) family is an example of a complex immune evasion system of S. aureus. Recently, we reported that SSL11 mediates motility arrest in human neutrophils by inducing cell adhesion. Our preliminary studies showed that SSL11 interacted with recombinant integrins, and integrin blocking antibodies inhibited SSL11-induced cell adhesion and motility arrest. The main goals of this study are: To determine how SSL11 induces cell adhesion via integrins (aim 1); To determine whether SSL11 inhibits pneumonia by inhibiting neutrophil migration in a mouse model (aim 2). This proposal is designed to characterize a previously under-appreciated mechanism of bacterial toxin action to evade neutrophil function, provide insight into how S. aureus establishes and maintains host colonization, and reveal a potential new therapy to treat pneumonia associated with massive neutrophil migration.