One of the organizing principles of the innate immune system is to recognize and react to """"""""microbial nonself', dependent on the existence of microbial-specific """"""""pattern molecules"""""""" that are not shared by host cells and the presence of host proteins, secreted and cell-associated, that recognize such indicators of invasion by microbes. The complex chemical structure and physical presentation of many of the microbial molecules subject to innate recognition have suggested a new paradigm in molecular recognition (""""""""pattern recognition"""""""") that has thus far defied concrete definition. The central hypothesis for our Program is that structural determinants of endotoxin dictate its recognition by and the subsequent response of the innate immune system to the microbe that it endows. We propose studies of the endotoxin of two organisms, Neisseria meningitidis and Francisella tularensis, as species that elicit nearly polarized host responses, the former dramatic proinflammatory changes and the latter successful evasion of host defense to invade phagocytes. To this end we have defined five projects: 1. Studies of the LPS and capsular antigen of F. tularensis 2. Mobilization and delivery of endotoxin to host targets 3. Structural determinants of protein-endotoxin interaction 4. Phagocyte and endothelial cell responses to endotoxin 5. Pathogenesis of F. tularensis Our integrated group of research projects, intimately linked to the Protein and Carbohydrate Chemistry Core for detailed chemical analysis, will elucidate critical features that influence the delivery, intracellular handling, and activation of target cells, notably phagocytes and endothelial cells. Such structure-function analyses will provide important and novel insights into fundamental principles of innate immune responses.
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