Citrobacter illuminates the mechanistic underpinnings of gut biogeography

柠檬酸杆菌阐明了肠道生物地理学的机制基础

• 批准号: 10027725
• 负责人: Andreas J Baumler
• 金额: $ 18.75万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10027725
• 关键词: Animal Model; Citrobacter; Citrobacter rodentium; Collection; Data; Ecosystem; Engineering; Environment; Environmental Risk Factor; Epithelial; Epithelium; Equilibrium; Etiology; Extinction (Psychology); Foundations; Goals; Growth; Habitats; Health; Homeostasis; Human; Hydrogen Peroxide; Infection; Light; Mediating; Microbe; Modeling; Mucous Membrane; Mucous body substance; Mus; Nutrient; Nutritional; Oxygen; Pathogenesis; Phase; Play; Process; Research; Research Personnel; Resources; Role; Shapes; Structure; Surface; Testing; Type III Secretion System Pathway; Virulence; Virulence Factors; Work; colon microbiota; dysbiosis; enteric pathogen; expectation; genetic manipulation; gut microbiota; host microbiota; host-associated microbial communities; human disease; innovation; insight; interest; knowledge of results; microbial; microbial community; microbiome research; microbiota; novel; pathogen; prevent; public health relevance; tool; trait

PROJECT SUMMARY The microbiota influences many aspects of human health, but the mechanisms that balance it remain incompletely understood. Our previous work has established the concept that enteric pathogens act as ecosystem engineers by using their virulence factors to manipulate host habitat filters, thereby constructing new nutrient-niches that support their invasion of the gut ecosystem. Thus, mucosal pathogens are valuable tools for identifying host-derived habitat filters that structure the microbiota. Our long-range goal is to identify host-derived habitat filters that shape the microbiota by using Citrobacter rodentium as a tool to identify environmental factors that allow the pathogen to edge out gut-associated microbial communities. The objectives of this application are to study how its main virulence factor, the type III secretion system (T3SS), helps C. rodentium to prevent pathogen extinction during the initial phase of infection. Our central hypothesis is that virulence factors provide C. rodentium with access to epithelial hydrogen peroxide, a host habitat filter that sustains pathogen growth early after infection. We will test different aspects of our hypothesis by determining whether intimate attachment mediated by the T3SS provides C. rodentium access to NOX1-derived hydrogen peroxide (H2O2) and determining the role NOX1-derived H2O2 plays as a habitat filter structuring the spatial organization of the gut microbiota. The proposed work makes innovative use of mucosal pathogens to provide fundamental insights into microbiome research and we expect that a successful completion will offer mechanistic insights into host habitat filters selecting for microbial traits that permit survival and growth in the host. By establishing the identity of a novel host-derived habitat filter, our research will be of wide appeal among researchers interested in microbial pathogenesis and the nutritional environment that shapes our host-associated microbial communities.

项目摘要 微生物群影响人类健康的许多方面，但平衡它的机制仍然存在 不完全理解。我们以前的工作已经建立了肠道病原体作为 生态系统工程师通过使用他们的毒力因子来操纵宿主栖息地过滤器，从而构建新的 支持它们入侵肠道生态系统的营养小生境。因此，粘膜病原体是有价值的工具， 识别构建微生物群的宿主来源的栖息地过滤器。我们的长期目标是识别宿主来源的 栖息地过滤器，通过使用啮齿柠檬酸杆菌作为识别环境因素的工具来塑造微生物群 使病原体排挤出肠道相关的微生物群落。本申请的目的是 研究其主要毒力因子III型分泌系统（T3SS）如何帮助C.防止啮齿动物 病原体在感染的初始阶段灭绝。我们的中心假设是，毒力因子提供了 C.啮齿类动物可以接触到上皮过氧化氢，这是一种宿主栖息地过滤器，可以维持病原体的早期生长 感染后我们将通过确定亲密依恋是否 由T3SS介导提供C.啮齿动物接触NOX 1衍生的过氧化氢（H2O2）， 确定NOX1衍生的H2O2作为构建肠道空间组织的栖息地过滤器的作用 微生物群这项拟议的工作创新性地利用了粘膜病原体，为以下方面提供了基本见解： 微生物组研究，我们希望成功完成将提供对宿主栖息地的机械见解 过滤器选择允许在宿主中存活和生长的微生物特征。通过建立一个 新的宿主来源的栖息地过滤器，我们的研究将广泛吸引感兴趣的研究人员在微生物 致病机制和营养环境，塑造我们的主机相关的微生物群落。