Mechanism of Colonization Resistance

抗殖民化机制

基本信息

批准号：
10594972
负责人：
Andreas J Baumler
金额：
$ 54.79万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-20 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10594972
关键词：
Antibiotic Therapy Antibiotics Bacteria Biology Butyrates Carbon Dioxide Cells Data Development Drug Targeting Engraftment Enterobacteriaceae Epithelium Equilibrium Fiber Funding Goals Growth Habitats Human body Hypoxia Immunocompromised Host Impairment Intestines Large Intestine Mediating Metabolism Microbe Modeling Modification Outcome Pathogenesis Pathogenicity Predisposition Production Property Research Research Personnel Resistance Resources Salicylic Acids Science Sepsis Shapes Signal Pathway Source Surface Testing Therapeutic Intervention Time Volatile Fatty Acids Work antibiotic resistant infections carbapenem-resistant Enterobacteriaceae colonization resistance drug development dysbiosis expectation experimental study gut microbiota host microbiota immune function infection risk innovation insight interest member microbial microbial community microbiome microbiota microbiota metabolites microorganism new therapeutic target non-typhoidal Salmonella novel novel strategies pathogen preservation prevent public health relevance trait

项目摘要

PROJECT SUMMARY Antibiotic treatment impairs colonization resistance, thereby increasing the risk of infection with Enterobacteriaceae that are frank (e.g. non-typhoidal Salmonella serovars) or opportunistic (e.g. carbapenem-resistant Enterobacteriaceae) pathogens. However, how the host contributes to colonization resistance against pathogenic Enterobacteriaceae remains incompletely understood. The host uses “habitat filters” to select for microbial traits permitting survival and growth in the host, thereby shaping composition, spatial organization and size of microbial communities. Our goal is to elucidate how the host contributes to colonization resistance against pathogenic Enterobacteriaceae and to develop approaches aimed at restoring this nonspecific immune function during antibiotic therapy. We hypothesize that a mechanistic understanding of how the host contributes to colonization resistance against pathogenic Enterobacteriaceae will facilitate the development of drugs that target host signaling pathways to strengthen colonization resistance. We will test different aspects of our hypothesis in two specific aims. Specific Aim 1 will identify resources that a shift in epithelial metabolism provides for pathogenic Enterobacteriaceae to overcome niche modification by microbiota-derived short-chain fatty acids. Specific Aim 2 will provide a proof-of-principle for the idea drugs targeting the host can strengthen colonization resistance, thus making it possible to preserve this nonspecific immune function during active antibiotic therapy. Successful completion of the proposed work will provide mechanistic insights into a key function of the microbiome, which will be of wide appeal among researchers interested in microbial pathogenesis, microbiota research, and intestinal biology.

项目摘要抗生素治疗会损害定殖抗性，从而增加感染的风险弗兰克（例如非脉络性沙门氏菌血清射手）或机会主义（例如，抗碳青霉烯肠杆菌科病原体。但是，主机如何贡献对病原肠杆菌科的定殖抗性仍未完全理解。宿主使用“栖息地过滤器”来选择微生物性状，允许生存和生长主机，从而塑造组成，空间组织和微生物群落的大小。我们的目标是阐明宿主如何对致病性造成定殖抗性肠杆菌科并开发旨在恢复这种非特异性免疫的方法抗生素治疗期间的功能。我们假设对机械的理解宿主有助于对致病肠杆菌科的定殖性抗性靶向宿主信号通路以增强定殖的药物的开发反抗。我们将以两个具体目标来检验假设的不同方面。具体目标1 将确定上皮代谢的转变为致病性提供的资源肠杆菌科以克服微生物衍生的短链脂肪酸来克服利基修饰。特定的目标2将为瞄准宿主的想法药物提供原理证明可以增强定殖抗性，因此可以保留这种非特异性免疫功能在主动抗生素治疗期间。成功完成拟议的工作将提供对微生物组的关键功能的机械洞察力，这将在外观中广泛对微生物发病机理，微生物群研究和肠生物学感兴趣的研究人员。