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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：
10494296
负责人：
PAULA I WATNICK
金额：
$ 69.79万
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/10494296
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.

抽象/项目总结