Epithelial intrinsic inflammasomes direct host defense against gut microbes

上皮内在炎症小体直接引导宿主防御肠道微生物

基本信息

批准号：
10428520
负责人：
Leigh Knodler
金额：
$ 8.34万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10428520
关键词：
Acute CASP1 gene Caspase Cell Death Cells Child Chronic Dendritic Cells Development Diarrhea Disease Enterocytes Epithelial Epithelial Cells Event Exhibits Family Gastrointestinal tract structure Glycoproteins Goblet Cells Gut Mucosa Homeostasis Host Defense Immune Immune response In Vitro Infection Inflammasome Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Innate Immune Response Interferon Type II Interleukin-1 beta Interleukin-18 Intervention Intestinal Mucosa Intestines Invaded Knowledge Lamina Propria Lead Lectin Lytic Mediating Mediator of activation protein Microbe Modeling Morbidity - disease rate Mucins Mucous Membrane Mucous body substance Multiprotein Complexes Nausea Pain Pathway interactions Regulation Research Role Salmonella typhimurium Signal Transduction Stimulus Surface Testing Therapeutic Viral antimicrobial cytokine defense response defined contribution enteric infection enteric pathogen fight against gastrointestinal epithelium gastrointestinal infection gut microbes in vivo intestinal epithelium knock-down macrophage microbial microbial host monolayer mortality neutrophil pathogen prevent rational design recruit resistin response sensor

项目摘要

PROJECT SUMMARY Enteric infections and their associated sequelae, including pain, nausea, inflammation and diarrhea, are major causes of morbidity and mortality worldwide, particularly in children. Being at the frontline of intestinal host defense, intestinal epithelial cells (IECs) are the frequent target of enteric pathogens. It is generally believed that during enteric infections, the gut epithelium and overlying mucus layer, which are at the forefront of the host-microbial interface, primarily provide a physical barrier against invading pathogens, whereas any innate immune response that occurs within the intestinal mucosa is largely driven by the immune/inflammatory cells resident in the lamina propria. In contrast, recent studies, including our own, ascribe an unprecedented role for IECs as important players in gut innate immune responses. Together, these studies unequivocally showed that canonical and non-canonical inflammasomes in IECs promote host defense and inflammatory responses at early stages of infection by the model enteric pathogen, Salmonella enterica serovar Typhimurium. The primary objective of this application is to define the contribution of IEC inflammasomes to antimicrobial host defenses in the gut. Our general hypothesis is that IEC intrinsic inflammasomes coordinate several protective and anti-microbial pathways at the gut mucosal surface. Two integrated specific aims are proposed to test this hypothesis. First, we will delineate the protective role of IEC inflammasomes against enteric pathogens in vitro and in vivo, and assess the regulation and temporal contribution of IEC canonical and non-canonical inflammasomes during infection. Second, we will elucidate goblet cell-specific inflammasome-dependent defense responses. Completion of this proposal will close a significant knowledge gap regarding the impact of epithelium-intrinsic inflammasomes on intestinal antimicrobial defense, homeostasis and disease development.

项目概要肠道感染及其相关后遗症，包括疼痛、恶心、炎症和腹泻，是主要的全世界尤其是儿童发病和死亡的原因。站在肠道宿主的最前线肠道上皮细胞（IEC）是肠道病原体的常见目标。人们普遍认为在肠道感染期间，肠道上皮和上面的粘液层位于肠道的最前部。宿主-微生物界面，主要提供针对入侵病原体的物理屏障，而任何先天的肠粘膜内发生的免疫反应很大程度上是由免疫/炎症细胞驱动的居住于固有层。相比之下，最近的研究，包括我们自己的研究，都赋予了前所未有的作用 IEC 作为肠道先天免疫反应的重要参与者。总之，这些研究明确表明 IEC 中的典型和非典型炎症小体促进宿主防御和炎症反应模型肠道病原体、鼠伤寒沙门氏菌感染的早期阶段。这本申请的主要目的是确定 IEC 炎症小体对抗菌宿主的贡献肠道内的防御。我们的一般假设是 IEC 内在炎症小体协调多种保护作用以及肠道粘膜表面的抗菌途径。提出了两个综合的具体目标来测试这一点假设。首先，我们将在体外描述 IEC 炎症小体对肠道病原体的保护作用和体内，并评估 IEC 规范和非规范的调节和时间贡献感染期间的炎症小体。其次，我们将阐明杯状细胞特异性炎症小体依赖性防御反应。该提案的完成将弥补关于影响的重大知识差距上皮固有炎症小体对肠道抗菌防御、稳态和疾病发展的影响。