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

• 批准号: 10202411
• 负责人: Leigh Knodler
• 金额: $ 43.17万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202411
• 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 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; design; enteric infection; enteric pathogen; fight against; gastrointestinal epithelium; gastrointestinal infection; gut microbes; in vivo; inflammatory disease of the intestine; intestinal epithelium; knock-down; macrophage; microbial; microbial host; monolayer; mortality; neutrophil; pathogen; prevent; recruit; resistin; response; sensor

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.

项目总结 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 世界范围内的发病率和死亡率，特别是儿童的发病率和死亡率。站在肠道宿主的第一线 防御方面，肠上皮细胞(IECS)是肠道病原体的常见靶标。人们普遍认为， 在肠道感染期间，位于肠道最前端的肠道上皮和覆盖的粘液层 宿主-微生物界面，主要提供一种物理屏障来抵御入侵的病原体，而任何先天的 肠粘膜内发生的免疫反应主要是由免疫/炎症细胞驱动的 驻留在固有层。相比之下，最近的研究，包括我们自己的研究，将前所未有的作用归因于 IECs在肠道先天免疫反应中发挥重要作用。总而言之，这些研究明确表明 IEC中的典型和非典型炎性小体促进宿主防御和炎症反应 由模式肠道病原体鼠伤寒沙门氏菌感染的早期阶段。这个 本申请的主要目的是确定IEC炎性小体对抗菌宿主的贡献 肠子里的防御。我们的一般假设是，IEC内在的炎性小体协调了几个保护性 以及肠道粘膜表面的抗微生物途径。提出了两个综合的具体目标来检验这一点 假设。首先，我们将描述IEC炎性小体在体外对肠道病原体的保护作用。 和在体内，并评估IEC规范和非规范的调节和时间贡献 感染过程中的炎性小体。第二，我们将阐明杯状细胞特异性炎症体依赖 防御反应。这项提案的完成将弥合关于以下影响的重大知识差距 上皮源性炎症小体对肠道抗菌防御、体内平衡和疾病发展的影响。