Regulation of intestinal barrier by E. coli curli fibrils

说明(申请人提供)：淀粉样蛋白是细菌生物膜的一种常见成分，由杆菌、细菌和变形杆菌产生。最近，我们发现肠道细菌生物膜中发现的一种淀粉样蛋白Curli通过Toll样受体2(TLR2)/TLR1复合体被天然免疫系统识别。陆军外科医生Alfred Nissle博士从一名士兵的粪便中分离出了大肠杆菌Nissle 1917(Nissle)，这名士兵在第一次世界大战期间爆发了严重的志贺氏菌，但没有出现腹泻。此后，许多研究调查了这种细菌用于益生菌治疗的可能性。 在炎症性肠病(IBD)中。临床试验表明，在预防溃疡性结肠炎(UC)复发方面，ECN的治疗与标准药物治疗一样有效。随后的研究发现，尼斯莱增强了肠道上皮屏障功能。此外，Nissle激活TLR2已被证明在胃肠道具有免疫调节作用。然而，ECN导致后一种影响的机制仍不清楚。这项应用的目的是调查细菌淀粉样蛋白对宿主肠道免疫反应的贡献。我们假设，通过TLR2在胃肠道中检测到细菌淀粉样蛋白，使上皮细胞能够作为细菌从肠腔移位的哨兵，并通过增强上皮屏障来做出反应。我们将通过研究共生生物体Nissle产生的卷曲纤维的免疫调节功能来验证这一假设。

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.