198 TNF directs protective neutrophil and IL-17+ γδ T cell responses against Staphylococcus aureus skin infections

Abstract

Staphylococcus aureus is the leading cause of skin and soft tissue infections and has become a major health burden due to the emergence of antibiotic-resistant strains. To develop alternative therapies to antibiotics, we sought to understand the protective immune mechanisms against S. aureus skin infections mediated by tumor necrosis factor (TNF). TNF is a proinflammatory cytokine that is rapidly induced upon S. aureus exposure and whose inhibition is associated with increased risk of S. aureus infections in humans. However, the contribution of TNF or the cognate receptors, TNFR1 and TNFR2, to host defense against S. aureus skin infections is unclear. Therefore, to determine the host defense role of TNF, we used an in vivo mouse model of S. aureus skin infection whereby TNF, TNFR1, or TNFR2 deficient mice and wildtype (wt) mice were intradermally injected with bioluminescent S. aureus and monitored for 14 days. TNF, TNFR1, and TNFR2 deficient mice exhibited increased lesion sizes and bacterial burden compared to wt mice, suggesting TNF is important against S. aureus skin infections and TNFR1 and TNFR2 have non-redundant roles in TNF-mediated immunity. Since TNF has been reported to contribute to neutrophil trafficking and IL-17 expression, we hypothesized that TNF promotes the previously identified protective neutrophil abscess formation and IL-17+ γδ T cell responses against S. aureus skin infection. In fact, TNF deficient mice had significantly impaired neutrophil recruitment, abscess formation, and diminished skin-infiltrating IL-17+ γδ T cells compared to wt mice. Taken together, these findings indicated that differential TNF signaling by TNFR1 and TNFR2 directs protective neutrophil and IL-17+ γδ T cell responses during S. aureus skin infections, which has implications in the development of novel immune-based therapies as alternatives to antibiotic treatment against S. aureus and potentially other bacterial infections.