Control of intestinal innate immunity by the commensal microbiota in a model host

模型宿主中共生微生物群对肠道先天免疫的控制

• 批准号: 10360733
• 负责人: PAULA I WATNICK
• 金额: $ 71.98万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-24 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10360733
• 关键词: Acetates; Androgen Receptor; Animal Model; Arthropods; Bacteria; Cells; Chromatin Remodeling Factor; Chronic; Circadian Rhythms; Communities; Conserved Sequence; Data; Dependence; Development; Diabetes Mellitus; Disease; Disease susceptibility; Drosophila genus; Drosophila melanogaster; Enterocytes; Enteroendocrine Cell; Epithelial; Epithelial Cells; Fermentation; Genetic; Genetic Transcription; Goals; Health Promotion; Histones; Home; Homeostasis; Immune; Immune response; Immune signaling; Immunologic Deficiency Syndromes; Infection; Ingestion; Innate Immune Response; Innate Immune System; Intestines; Laboratories; Learning; Link; Lipids; Malnutrition; Mammals; Mediating; Metabolic; Metabolic Diseases; Microbe; Modeling; Modernization; Names; Natural Immunity; Nuclear; Nutrient; Obesity; Oral; Pathway interactions; Peptide Synthesis; Peptides; Peptidoglycan; Predisposition; Probiotics; Protein Acetylation; Proteins; Proteomics; Regulatory Pathway; Research; Resistance to infection; Role; Satiation; Seminal; Signal Pathway; Signal Transduction; TNF gene; Testing; Time; Transcriptional Activation; Transcriptional Regulation; Transgenic Organisms; Variant; Vibrio cholerae; Vibrio cholerae infection; Work; antimicrobial peptide; cell type; chromatin remodeling; chronic infection; colonization resistance; commensal bacteria; commensal microbes; cytokine; design; dysbiosis; ecdysone receptor; enteric infection; enteric pathogen; experimental study; fly; gut microbiota; histone acetyltransferase; innate immune function; insulin signaling; intestinal epithelium; lipid metabolism; microbial; microbial community; microbiota; novel; pathogen; pathogenic bacteria; prebiotics; prevent; receptor; response; small molecule; stem; stem cells; therapy development; tool; uptake; wasting

Abstract/Project Summary Microbes interact with the intestinal epithelium in ways that modulate susceptibility to infection, malnutrition, and predisposition to chronic metabolic diseases such as obesity and diabetes. However, the host signaling pathways utilized by microbes to promote health and disease are poorly understood. The powerful genetic tools provided by the model arthropod Drosophila melanogaster have enabled many discoveries that form the basis of our modern understanding of innate immunity. Here we propose to exploit the Drosophila melanogaster model to define the host signaling pathways that detect intestinal microbes and orchestrate the innate immune response of the intestinal epithelium. Drosophila intestinal stem cells, enterocytes and enteroendocrine cells (EECs) carry out functions similar to those of the mammalian intestine. EECs, which constitute 5-10% of cells in the intestinal epithelium, secrete enteroendocrine peptides (EEPs) that modulate host metabolic functions such as insulin signaling, satiety, and intestinal contractions. We have identified a subset of EECs that responds uniquely to the microbial fermentation product acetate by activating innate immune signaling through the TNF-like Immunodeficiency (IMD) pathway. In these EECs, IMD signaling increases transcription of the genes encoding EEPs. These EEPs, in turn, coordinate the response of the diverse cell types in the intestine to microbes. Here we investigate the mechanism by which microbes activate the intestinal innate immune response and the ultimate impact of this regulatory pathway on susceptibility to infection. In this proposal, we will investigate the role of chromatin remodeling in acetate-mediated IMD signaling, the contribution of peptidoglycan to intestinal IMD signaling, the role of EEPs as cytokines, and finally the cell- specific roles of EEPs in modulating susceptibility to intestinal infection. The overarching objective of this research is to uncover novel paradigms of the intestinal innate immune response to microbes with the goal of informing therapies that modify nutrient utilization in malnutrition, chronic metabolic diseases and susceptibility to intestinal infection.

摘要/项目摘要 微生物与肠上皮细胞相互作用，调节对感染，营养不良， 以及易患慢性代谢疾病如肥胖症和糖尿病。然而，主机信令 微生物利用的促进健康和疾病的途径知之甚少。强大的基因 模式节肢动物黑腹果蝇提供的工具使许多发现成为可能， 我们对先天免疫的现代理解的基础。在这里，我们建议利用果蝇 黑胃模型来定义宿主信号通路，该信号通路检测肠道微生物并协调 肠上皮的先天免疫反应。 果蝇肠干细胞、肠上皮细胞和肠内分泌细胞（EECs）执行类似于 哺乳动物的肠道。占肠上皮细胞5-10%的内皮细胞分泌 肠内分泌肽（EEPs）调节宿主代谢功能，如胰岛素信号传导、饱腹感和 肠道收缩我们已经确定了一个独特的响应微生物的EEC的子集， 发酵产物乙酸通过激活先天免疫信号通过TNF样免疫缺陷 (IMD)通路在这些EEC中，IMD信号增加编码EEP的基因的转录。这些 反过来，EEPs协调肠道中不同细胞类型对微生物的反应。这里我们 研究微生物激活肠道先天免疫反应的机制， 这一调节途径对感染易感性的影响。 在这个提议中，我们将研究染色质重塑在醋酸盐介导的IMD信号传导中的作用， 肽聚糖对肠道IMD信号传导的贡献，EEPs作为细胞因子的作用，最后是细胞- EEPs在调节肠道感染易感性中的特殊作用。本报告的总体目标 研究的目的是揭示肠道对微生物的先天免疫反应的新模式， 为改变营养不良、慢性代谢疾病和易感性的营养利用的疗法提供信息 肠道感染