The lipid A moiety of lipopolysaccharides (LPS) initiates the production of a variety of host-derived inflammatory mediators that result in inflammation, including the clinical symptoms of septic shock. Recent studies have demonstrated that the structure of lipid A varies considerably among Gram-negative bacteria, and that these variations account for key differences in the inflammatory responses of the host. Emerging data indicates that these differences in responses are due to differential use of two cell signaling cascades initiated by recruitment of the adaptor proteins MyD88 or TRIP to the intracellular domain of the cell surface receptor TLR4. The objective of this application is to link specific structural features of Escherichia coli and Salmonella typhimurium lipid A with signal initiation (either MyD88 and/or TRIP recruitment), patterns of inflammatory mediator production, signaling pathways utilized, and gene expression profiles. The objective will be achieved by pursuing 3 Specific Aims designed to provide a range of chemically synthesized lipid A molecules, and to evaluate the capacity of each to induce and regulate inflammatory function. The driving rationale for this project is that until well-defined, synthetic lipid A derivatives are available, it will not be possible to identify the structural features of lipid A responsible for the activation of MyD88- and TRIF- dependent cell signaling pathways leading to differential activation of innate immune responses. By completing the proposed studies, we will substantially increase our understanding of structure-function relationships within lipid A of two clinically important bacterial species. We will have demonstrated that structurally different lipid As induce distinct inflammatory responses based on their potency for initiating cellular activation through the MyD88-dependent, TRIF-dependent, or both pathways. In addition, a database will have been produced of structural features linked to signal initiation data, the pattern of cytokines induced, and the temporal activation of intermediate signal transduction and gene expression induced by each synthetic compound. This database will guide the development of structurally defined lipid A compounds for specific immune modulating applications. ? ? ?
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