Signaling through intestinal MUC receptors by bacterial Serine Proteases of Enterobacteriaceae

摘要 肠聚集性大肠埃希菌(EAEC)和黏附性侵袭性大肠杆菌(AIEC)都与 临床和亚临床炎症。肠出血性肠杆菌是引起旅行者腹泻的重要病原体， 工业化国家和发展中国家的增长步履蹒跚。临床结果表明，宿主 炎症反应在EAEC病理中起着重要作用，因为促炎因子水平的升高 炎性标志物，包括白介素8、白介素1β、粪便乳铁蛋白和白细胞渗出 在感染EAEC的个人中发现。最重要的是，即使是感染EAEC的无症状患者也是 被发现表现出生长迟缓和肠道炎症。另一方面，AIEC被牵连到 炎症性肠病(IBD)的发病机制常被发现与炎症性肠病有关 肠粘膜。持续感染AIEC会导致慢性炎症和肠道纤维化。 然而，与感染这些病原体期间的炎症反应有关的罪魁祸首是 不能完全理解。越来越多的证据表明，细菌腔蛋白水解酶的活性和激活 蛋白酶受体最终导致动物肠道通透性增加和结肠炎加重 模特和人类。在这一点上，我们的数据表明，蛋白酶属于丝氨酸蛋白酶 肠杆菌科(Spates)家族的自身转运蛋白通过结合与炎症过程相关 和裂解跨膜信号粘蛋白(MUC)。我们的总体假设是有粘蛋白溶解的 在细菌感染期间，活动通过靶向肠道MUC受体而引发肠道炎症。 该项目由三个具体目标组成。在目标1中，我们将描述信号通路的特征 C2S通过肠道MUC受体使用人类结肠素激活。在目标2中，我们将调查是否 哺乳动物的凝集素、脱落酶和Spate使用相同的机制来激活MUC受体，如果它们 触发类似的信号通路。在目标3中，我们将研究SPATS在糖尿病发病机制中的作用。 EAEC和AIEC在MUC受体信号传导的背景下。我们将利用实验系统和 在当前项目下发展的协作，以将这种理解提高到可操作的水平，并确定 有希望的主导干预措施。

Abstract Both, Enteroaggregative Escherichia coli (EAEC) and Adherent-Invasive E. coli (AIEC) are associated with clinical and subclinical inflammation. EAEC is an important pathogen of traveler's diarrhea, diarrhea in industrialized countries and growth faltering in developing countries. Clinical findings suggest that the host inflammatory responses play a substantial role in EAEC pathology given that elevated levels of pro- inflammatory markers, including interleukin (IL)-8, IL-1β, fecal lactoferrin and leukocyte infiltrates are often found in EAEC-infected individuals. Most importantly, even asymptomatic patients infected with EAEC were found to exhibit growth retardation and intestinal inflammation. On the other hand, AIEC has been implicated in the pathogenesis of the Inflammatory Bowel Disease (IBD) and it is often found adhered to the inflamed intestinal mucosa. Persistent infection with AIEC leads to chronic inflammation and intestinal fibrosis. Nevertheless, the culprits associated with the inflammatory response during infection with these pathogens are not entirely understood. Increasing evidence suggests that bacterial luminal protease activity and activation of protease receptors ultimately results in increased intestinal permeability and exacerbation of colitis in animal models and in human. In this regard, our data suggest that proteases belonging to the serine protease autotransporter of Enterobacteriaceae (SPATEs) family are associated with inflammatory processes by binding and cleaving transmembrane signaling mucins (MUC). Our overall hypothesis is that SPATEs with mucinolytic activity trigger intestinal inflammation by targeting intestinal MUC receptors during bacterial infections. This project is comprised by three specific Aims. In Aim 1, we will characterize the signaling pathways activated by C2S through intestinal MUC receptors using human colonoids. In Aim 2, we will investigate if mammalian lectin, sheddases and SPATEs use the same mechanism to activate MUC receptors and if they trigger similar signaling pathways. In Aim 3, we will investigate the role of SPATEs in the pathogenesis of EAEC and AIEC in the context of MUC receptor signaling. We will leverage the experimental systems and collaborations developed under current projects to take this understanding to an actionable level and identify promising lead interventions.