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: 10527730
• 负责人: Fernando Ruiz
• 金额: $ 27.21万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527730
• 关键词: Age; Animal Model; Apoptosis; Bacterial Infections; Binding; Biochemical; Bioinformatics; Cell Communication; Cell physiology; Cells; Chronic; Citrobacter; Clinical; Colitis; Collaborations; Confocal Microscopy; Data; Developed Countries; Developing Countries; Diarrhea; Enteral; Enterobacteriaceae; Epithelial; Epithelial Cells; 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; Lead; Lectin; Leukocytes; 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; base; 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.

摘要 肠聚集性大肠杆菌（EAEC）和粘附侵袭性大肠杆菌（E。大肠杆菌（AIEC）与 临床和亚临床炎症。EAEC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， 炎症反应在EAEC病理学中起重要作用， 炎症标志物，包括白细胞介素（IL）-8，IL-1β，粪便乳铁蛋白和白细胞浸润， 在感染EAEC的个体中发现。最重要的是，即使是感染EAEC的无症状患者， 表现出生长迟缓和肠道炎症。另一方面，AIEC被卷入了 炎症性肠病（IBD）的发病机制，它经常被发现粘附在发炎的 肠粘膜AIEC的持续感染导致慢性炎症和肠纤维化。 然而，在感染这些病原体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肠道通透性增加和结肠炎恶化 模型和人类。在这方面，我们的数据表明，蛋白酶属于丝氨酸蛋白酶 肠杆菌科自转运蛋白（SPATEs）家族通过结合 和切割跨膜信号传导粘蛋白（MUC）。我们的总体假设是， 活性通过在细菌感染期间靶向肠道MUC受体而触发肠道炎症。 该项目由三个具体目标组成。在目标1中，我们将描述 使用人类结肠通过肠MUC受体由C2 S激活。在目标2中，我们将研究 哺乳动物凝集素、脱落酶和SPATE使用相同的机制来激活MUC受体，并且如果它们 触发类似的信号通路。在目标3中，我们将研究SPATE在糖尿病发病机制中的作用。 MUC受体信号传导背景下的EAEC和AIEC。我们将利用实验系统， 在当前项目下开展合作，将这种理解提高到可操作的水平，并确定 有希望的铅干预措施。