How S. aureus protein SSL11 inhibits neutrophil migration

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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 lack of an effective vaccine. Secondary infections occur in approximately 10% to 30% of cases in hospitalized, severely ill COVID-19 patients, with much greater frequency in the ICU setting. This is confirmed by a case report that a young man without underlying conditions passed a with SARS-Cov-2 and MRSA co-infection with severe pneumonia. Unlike other bacterial pathogens, S. aureus colonizes about 30% of the human population. Although S. aureus colonization is associated with higher risks for S. aureus clinical infections, most colonized individuals will not experience S. aureus infections. How S. aureus transitions between colonization and pathogenesis remain unclear. During pulmonary infection, the 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 study showed that SSL11 interacted with recombinant integrins and integrins 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 explore the ability to engineer the SSL-derived peptides to inhibit pneumonia associated with massive neutrophil infiltration such as pneumonia (aim 2). The outcomes of this study will shed light on a new mechanism of bacterial toxin action to evade neutrophil function, will provide insight into how S. aureus establishes/maintains host colonization, and will provide a potential new therapy against pneumonia.