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：
10687173
负责人：
PAULA I WATNICK
金额：
$ 69.94万
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/10687173
关键词：
Acceleration Acetates Acetylation Androgen Receptor Arthropods Bacteria Cells Chromatin Modeling Chromatin Remodeling Factor Chronic Circadian Rhythms Communication Communities Conserved Sequence Data Dependence Development Diabetes Mellitus Disease Drosophila genus Drosophila melanogaster Enterocytes Enteroendocrine Cell Epithelium Fermentation Genetic Genetic Transcription Goals Health Promotion Histones Home Homeostasis Homologous Gene Immune Immune response Immune signaling Immunologic Deficiency Syndromes Infection Ingestion Innate Immune Response Innate Immune System Intestines Invaded 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 model organism 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/项目摘要微生物与肠上皮相互作用，调节对感染、营养不良、以及肥胖和糖尿病等慢性代谢疾病的易感性。然而，主机信号人们对微生物促进健康和疾病的途径知之甚少。强大的基因模型节肢动物果蝇提供的工具促成了许多发现，这些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黑腹果蝇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。果蝇肠干细胞、肠上皮细胞和肠内分泌细胞 (EEC) 执行与那些哺乳动物的肠道。 EEC 占肠上皮细胞的 5-10%，分泌肠内分泌肽 (EEP) 调节宿主代谢功能，例如胰岛素信号传导、饱腹感和肠道收缩。我们已经确定了 EEC 的一个子集，它对微生物有独特的反应通过类 TNF 免疫缺陷激活先天免疫信号，从而产生发酵产物醋酸盐（IMD）途径。在这些 EEC 中，IMD 信号传导会增加编码 EEP 的基因的转录。这些 EEP 反过来协调肠道内不同细胞类型对微生物的反应。在这里我们研究微生物激活肠道先天免疫反应的机制以及最终的作用该调节途径对感染易感性的影响。在本提案中，我们将研究染色质重塑在乙酸盐介导的 IMD 信号传导中的作用，即肽聚糖对肠道 IMD 信号传导的贡献、EEP 作为细胞因子的作用，以及最后的细胞- EEP 在调节肠道感染易感性方面的特殊作用。本次活动的总体目标是研究的目的是发现肠道对微生物的先天免疫反应的新范例，目的是为改变营养不良、慢性代谢疾病和易感性的营养利用的疗法提供信息到肠道感染。