The role of curli fibrils in modulating immune responses in the gut

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DESCRIPTION (provided by applicant): Amyloids are protein deposits that possess a conserved fibrillar cross-¿ sheet quartenary structure. More than 60 different amyloidogenic proteins are produced in humans. While the function of few of these proteins has been demonstrated including, islet-amyloid polypeptide and several peptide hormones, the role of many other amyloids remain unknown. Interestingly, few bacteria have been shown to produce amyloids. Curli fibers found in the biofilms of enteric bacteria including Escherichia coli and Salmonella enterica serovar. Typhimurium are the best-characterized bacterial amyloid to date. Recently, we discovered that Toll-like receptor (TLR) 2 recognizes both ¿-amyloid 1-42, a host amyloid, and curli amyloid fibers due to their conserved common ¿-sheet structure (19, 20). Moreover, we and others demonstrated that the dimerization of TLR2 with TLR1 is necessary for the recognition of ¿-amyloid 1-42 and curli amyloid fibers (21). TLR2 expressed by the intestinal epithelial cells contribute to the regulation of the intestinal barrier function (5). Nonetheless, the affects of amyloids on the intestinal epithelial barrier remain unknown. With this application we will investigate the contribution of bacterial and host amyloids to intestinal immune responses. Our central hypothesis is that the detection of amyloids via the TLR2/TLR1 complex generates a protective immune response in the gut epithelium leading to reinforcement of the intestinal epithelial barrier via activation of the PI3K pathway. This, in turn, leads to an increase in tight junction proteins. We will test our hypothesis using the commensal organism E. coli Nissle, as well as purified curli fibers and serum amyloid A1 (SAA1), a host amyloid produced in the gut upon inflammation. The rationale for the proposed research is that a better understanding of the mechanisms by which curli fibers of Nissle or host amyloid SAA promote epithelial barrier function will lead to a better mechanistic understanding of how intestinal epithelial barrier is regulated by the immune system during homeostasis and inflammation.