Sepsis may result in to 250,000 deaths annually in the United States. The development of septic shock in sepsis accounts for many of these deaths. Septic shock results from dysregulation of the innate immune response to infection. Past studies have focused on Gram- negative (G-) bacteria emphasizing the role of bacterial endotoxin (LPS) in the pathogenesis of the disease. Basic and clinical studies with LPS have revealed many fundamental mechanisms of the innate immune system. In contrast few studies mechanistic studies have been performed with Gram-positive (G+) organisms. This has primarily occurred because of doubts about the importance of G+ bacteria in septic shock. Now leaders in the field recognize that G+ infection is likely to be an important cause of septic shock. A currently held view is that there are overlapping an distinct immune/inflammatory responses to G- and G+ organisms. Unfortunately few efforts have been made to dissect the molecular mechanisms of the innate immune response to G+ bacteria. Here we describe experiments to bridge this significant gap in out knowledge. To do this we propose a series of studies to define the structure and function of Toll-like receptor 2 (TLR2), the receptor for G+ bacteria. We will use quantitative biochemical and molecular biological approaches in studies to address the four Specific Aims proposed herein.
Our Aims speak to our major long-term goal; to fully define the composition of TLR2 receptor complex and to identify key steps in the earliest signaling events that ultimately control gene expression. In addition we will also use mice containing gene deletions of key TLR family members in the cecal ligation model of bacteremia. The goal of the latter studies is to better understand the interrelationships among the various TLRs in the setting of bacteremia. The data provided by our studies will lead to a new understanding of the pathophysiogical responses to sepsis through an understanding of the basic mechanisms of the innate immune response. By doing this we hope to identify new therapeutic targets and to highlight proteins to consider in future studies investigating the genetic basis of septic shock.
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