Infection by microbial pathogens sets in motion a chain of events in innate immune system that help to contain infection before the acquired immune response develops its maximum efficacy. This process is triggered when proteins known as Toll-like receptors (TLRs) detect specific patterns of molecules derived from bacteria. Engagement of TLRs helps initiate signaling cascades that result in production of inflammatory cytokines, some of which, such as IL-1 may cause severe injury, shock, and death, if not controlled. Accordingly, our research focuses on elucidation of the molecular events that allow cells to recognize pathogens, with particular emphasis on lipopolysacharide (LPS), the most abundant and toxic activator of innate immunity. The primary TLR responsible for most LPS responses is Tlr4. There is a good deal of evidence that LPS directly binds to Tlr4. However, the composition of so called “LPS-cluster” is poorly understood. To further investigate LPS response in vivo and to reveal unknown components of LPS signaling pathway, we are using forward genetics approach and are analyzing LPS response in inbred and wild-derived strains of mice. Such analysis allows us to map additional loci that might be involved in LPS response. In addition to this analysis, we are using reverse genetics approach to further investigate the receptor properties of Tlr4. In order to do this, transgenic mice with mutant forms of Tlr4 are being generated. Analysis of the LPS response in transgenic animals will help to map potential LPS-binding sites and to elucidate interaction of TIR domain of Tlr4 with several cytoplasm adaptor molecules. Understanding of how Tlr4 works will permit to explain independent activation of different pathways proximal to Tlr4 and better predict the way to protect mammalian host from LPS-induced septic shock.

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