Sepsis is a disease with increasing morbidity and mortality that results from an uncontrolled inflammatory immune response initiated by the interaction of bacteria or bacterial components with host Toll-like receptors (TLRs). Bacterial-induced sepsis is associated with production of proinflammatory cytokines, expression of cell adhesion molecules, tissue damage, and in some cases death. Lipopolysaccaride (LPS) has been identified as a critical bacterial component in the pathogenesis of gram-negative sepsis. Current treatments focus on antibiotics for controlling infection and intensive care support for associated multi-organ failure. New treatment options are needed that address the unregulated inflammatory immune response. The A52R protein from vaccinia virus has been reported to inhibit production of proinflammatory cytokines in response to cell activation by a variety of TLR ligands. The protein was demonstrated to bind to intracellular signaling proteins common to TLRs. We have recently identified and characterized a peptide, termed P13, derived from the A52R protein, with similar properties as the parent protein. Studies conducted during the Phase I portion of this project demonstrated that peptide P13, i) inhibited the in vitro secretion of proinflammatory cytokines by endothelial cells and hepatocytes in response to LPS, ii) functioned in vivo to significantly reduce LPS-induced production of inflammatory mediators in the serum, and iii) enhanced survival in mice injected with LPS. The current Phase II SBIR proposal will expand these Phase I studies and define parameters for optimizing treatment with peptide P13 (specific aim #1), and provide a detailed assessment of the efficacy of peptide P13 in limiting inflammation and enhancing survival in endotoxin-induced sepsis (specific aim #2) and polymicrobial sepsis (specific aim #3). Establishing the efficacy of peptide P13 in both models of sepsis will provide a critical evaluation of the therapeutic potential of peptide P13. ? ? New treatment options are needed for patients with bacterial-induced sepsis, a disease with increasing morbidity and mortality. We have identified a novel anti-inflammatory peptide that has demonstrated feasibility to limit inflammation and disease development in an animal model of sepsis. Our current studies will provide a critical evaluation of the therapeutic potential of this peptide as a new treatment strategy for sepsis. ? ? ?
