Regulation of intestinal barrier by E. coli curli fibrils

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DESCRIPTION (provided by applicant): Amyloids, a common component of the biofilms of bacteria, are produced by the members of Bacteriodetes, Firmicutes and Proteobacteria. Recently, we have shown that curli, an amyloid found within the biofilms of enteric bacteria, is recognized by the innate immune system through Toll-like receptor 2 (TLR2)/TLR1 complex. E. coli Nissle 1917 (Nissle) was isolated by the army surgeon Dr. Alfred Nissle from the feces of a soldier who did not develop diarrhea during a severe Shigella outbreak during World War I. Since then many studies investigated the potential use of this organism for probiotic therapy in Inflammatory Bowel Diseases (IBD). Clinical trials have shown that treatment with EcN was as efficient as the standard medication in preventing the relapse of Ulcerativ Colitis (UC). Following studies have discovered that Nissle reinforces the intestinal epithelial barrier function. Furthermore, TLR2 activation by Nissle has been shown to have immunomodulatory effects in the gastrointestinal tract. Nonetheless, the mechanisms by which EcN induces the latter affects remain unknown. The objective of this application is to investigate the contribution of bacterial amyloids to host intesinal immune responses. We hypothesize that the detection of bacterial amyloids via TLR2 in the gastrointestinal tract enables epithelial cells to serve as sentinels for bacterial translocation fom the gut lumen and respond by augmenting the epithelial barrier. We will test this hypothesis by studying the immunomodulatory function of curli fibrils produced by the commensal organism Nissle.