339 Dynamic neutrophil and T cell TNF production protects against S. aureus skin infections

Abstract

Staphylococcus aureus (S. aureus) causes the majority of skin and soft tissue infections (SSTIs) with an annual burden of 14 million outpatient visits, 500,000 hospitalizations, and 4.2 billion dollars of inpatient costs in the U.S. alone. The widespread use of antibiotics to treat recurrent S. aureus has led to the emergence of methicillin-resistant S. aureus clinical isolates that have limited treatment options, creating a serious threat to public health. Better understanding of protective immunity to S. aureus SSTIs is imperative to develop effective therapies as an alternative to antibiotics. Tumor necrosis factor (TNF) is a proinflammatory cytokine that has been targeted to treat chronic inflammatory and autoimmune diseases. Interestingly, TNF inhibition decreases IL-17- and IFNγ-mediated bacterial host defense responses and results in an increased risk of S. aureus skin infections, implicating TNF in anti-staphylococcal immunity. Therefore, we evaluated the host defense role of TNF with an intradermal S. aureus skin infection model in TNF-deficient (TNF-/-) and wildtype (wt) mice, and discovered TNF-/- mice exhibited significantly increased lesion sizes and bacterial burdens compared to wt mice. Interestingly, neutrophils were the predominant source of TNF production early in the infection, whereas skin infiltrating CD4+ and γδ T cells increasingly contributed to TNF expression as well as IFNγ and IL-17 expression at later time points. Although CD4+ T cells constitutively expressed TNF and were the main source of IL-17 and IFNγ in the skin draining lymph nodes, there was a significantly higher number of TNF and IL-17 expressing γδ T cells than CD4+ T cells in the skin. Taken together, these findings suggest that TNF production has dynamic cellular and temporal components that regulate both innate and adaptive immunity against S. aureus skin infections.