Staphylococcus aureus is an opportunistic bacterial pathogen responsible for a diverse spectrum of human and animal diseases, including wound infections, osteomyelitis, endocarditis, and bacteremia leading to secondary abscesses in any of the major organ systems. Staphylococcal infections occur most frequently when mucosal barriers are breached, following insertion of a foreign body, or in the presence of other factors that compromise the immune system of the host. Currently, the host response to this organism is poorly understood. The majority of studies to date have focused on the role of PMNs modulating the host response to staphylococcal infections. S. aureus is typically classified as an extracellular pathogen that does not directly interact with the host immune system via T cells. However, we have shown that the staphylococcus produces a capsule with both free amino and negatively charged carboxyl groups that mediates its pathogenic potential in an experimental model of intraabdominal abscess formation in a T cell-dependent manner. This capsule can activate CD4+ T cells and induce the production of CXC chemokines, peptides that activate and recruit PMNs to sites of inflammation. The transfer of CD4+ T cells that have been activated by the S. aureus capsule promotes abscess formation in naive recipient animals. Based on these data, we hypothesize that CD4+ T cells activated by S. aureus capsules are critical in determining the outcome of staphylococcal infections through the release of CXC chemokines that control PMN trafficking to infected sites. This hypothesis will be tested in staphylococcal animal models of subcutaneous abscess formation and surgical wound infection. These models are clinically relevant, low-inoculum murine models of staphylococcal disease that mimic important aspects of human disease. We propose to: 1) Characterize the mechanism by which S. aureus synthesizes a capsule with a zwitterionic charge motif; 2) Evaluate the role of the capsular polysaccharide in the interaction between S. aureus and the host; 3) Determine the role of T cells in the pathogenesis of and host response to staphylococcal infections; and 4) Characterize the T cell-mediated CXC chemokine response to S. aureus infection and its role in regulation of PMN trafficking. Results from the proposed studies should provide insight regarding the under appreciated role of T cells in the pathogenesis and host response in S. aureus infections. This information may reveal new strategies for the prevention or treatment of S. aureus infections through immunomodulation of the host response to this organism.
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