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: 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
• 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

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