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

基本信息

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
项目类别：
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

项目摘要

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/项目摘要微生物以调节感染易感性，营养不良的方式与肠上皮相互作用易感性代谢性疾病，例如肥胖和糖尿病。但是，主机信令微生物利用来促进健康和疾病的途径知之甚少。强大的遗传模型节肢动物果蝇（Drosophila Melanogaster）提供的工具使许多发现形成了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 Melanogaster模型定义检测肠道微生物并协调的宿主信号通路肠上皮的先天免疫反应。果蝇肠道干细胞，肠上皮细胞和肠内分泌细胞（EEC）的功能类似哺乳动物肠的。 EEC占肠上皮细胞的5-10％的EEC，分泌调节宿主代谢功能（例如胰岛素信号，饱腹感和）的肠内分泌肽（EEPS）肠收缩。我们已经确定了一个对微生物的独特反应的EEC子集发酵产物乙酸盐通过通过TNF样免疫缺陷激活先天免疫信号传导（IMD）路径。在这些EEC中，IMD信号传导增加了编码EEP的基因的转录。这些 EEP反过来协调肠中各种细胞类型对微生物的响应。我们在这里研究微生物激活肠道免疫反应和最终的机制该调节途径对感染敏感性的影响。在此提案中，我们将研究染色质重塑在乙酸介导的IMD信号传导中的作用，肽聚糖对肠道IMD信号的贡献，EEP作为细胞因子的作用，最后是细胞 EEP在调节肠道感染的敏感性中的特定作用。这个总体目标研究是揭示肠道对微生物的肠道免疫反应的新范式，目的是告知修改营养不良，慢性代谢疾病和易感性的养分利用的疗法肠道感染。