Signaling through intestinal MUC receptors by bacterial Serine Proteases of Enterobacteriaceae

肠杆菌科细菌丝氨酸蛋白酶通过肠道 MUC 受体发出信号

• 批准号: 10626158
• 负责人: Fernando Ruiz
• 金额: $ 20.23万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-23 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10626158
• 关键词: Adherent Invasive Escherichia coli; Age; Animal Model; Apoptosis; Bacterial Infections; Binding; Biochemical; Bioinformatics; Cell Communication; Cell physiology; Cells; Chronic; Citrobacter; Clinical; Colitis; Collaborations; Colon; Confocal Microscopy; Data; Developed Countries; Developing Countries; Diarrhea; Enteral; Enterobacteriaceae; Epithelial Cells; Epithelium; Escherichia coli; Escherichia coli Infections; Exhibits; Extracellular Domain; Family; Gene Silencing; Genetic; Growth; Human; Impaired cognition; Individual; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Interleukin-1 beta; Interleukin-8; Intervention; Intestinal Fibrosis; Intestinal Mucosa; Intestinal permeability; Intestines; Lactoferrin; Lectin; Leucocytic infiltrate; Ligands; Link; MAP3K7 gene; Mass Spectrum Analysis; Membrane; Modeling; Molecular; Mucin 1 protein; Mucin-2 Staining Method; Mucins; Mucous Membrane; Mucous body substance; Outcome; Pathogenesis; Pathology; Patients; Penetration; Peptide Hydrolases; Persons; Play; Process; Productivity; Receptor Activation; Receptor Signaling; Regulation; Research; Role; Salmonella; Serine Protease; Shigella; Shigella flexneri; Signal Pathway; Signal Transduction; System; Thinness; Traveler' s diarrhea; Virulence Factors; chronic infection; diarrheal disease; enteric pathogen; enteroaggregative Escherichia coli; gut colonization; gut inflammation; inflammatory marker; insight; mucin receptor; pathogen; pathogenic Escherichia coli; receptor; response; tool; transcriptome sequencing

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.

抽象的 两者均与肠道大肠杆菌（EAEC）和粘附的大肠杆菌（AIEC）均与 临床和亚临床炎症。 EAEC是旅行者腹泻的重要病原体，腹泻 工业化国家并在发展中国家伪造。临床发现表明宿主 鉴于促进反应升高，炎症反应在EAEC病理学中起着重要作用 炎症标记，包括白介素（IL）-8，IL-1β，粪便乳铁蛋白和白细胞浸润通常是 在EAC感染的个体中发现。最重要的是，即使感染了EAEC的不对称患者也是 发现会提取生长迟缓和肠道注射。另一方面，已经暗示了AIEC 炎症性肠病（IBD）的发病机理，经常被发现遵守发炎 肠粘膜。持续感染AIEC会导致慢性感染和肠纤维化。 然而，这些病原体感染期间与炎症反应相关的罪魁祸首是 不完全理解。越来越多的证据表明细菌腔蛋白酶活性和激活 蛋白酶受体最终导致动物中肠道渗透性增加和结肠炎加剧 模型和人类。在这方面，我们的数据表明属于系列蛋白酶的蛋白酶 肠杆菌科（SPATES）家族的自转运蛋白通过结合与炎症过程有关 并切割跨膜信号粘蛋白（MUC）。我们的总体假设是粘液溶液 活性在细菌感染过程中靶向肠道MUC受体引发肠道感染。 该项目由三个特定目标完成。在AIM 1中，我们将表征信号通路 使用人类结构素通过肠道MUC受体激活C2。在AIM 2中，我们将调查是否 哺乳动物的讲座，Sheddase和Spates使用相同的机制激活MUC受体，以及它们是否 触发类似的信号通路。在AIM 3中，我们将研究Spates在 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 在当前项目下开发的合作，以将此理解提高到可行的水平并确定 有希望的铅干预措施。