Mechanisms Underlying Nutrient-Mediated Sporulation in C. difficile

艰难梭菌营养介导的孢子形成的机制

• 批准号: 10619583
• 负责人: SHONNA M. MCBRIDE
• 金额: $ 46.59万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619583
• 关键词: Affect; Atmosphere; Bacteria; Bacterial Infections; Biochemical; Biological Process; Cells; Clostridium; Clostridium difficile; Complex; Cues; Data; Development; Diarrhea; Dietary Intervention; Digestive System Disorders; Disease; Disinfectants; Energy-Generating Resources; Environment; Experimental Designs; Exposure to; Feces; Foundations; Gene Expression Regulation; Germination; Goals; Growth; Infection Control; Inflammatory; Influentials; Ingestion; Intestines; Investigation; Knowledge; Life Cycle Stages; Link; Mediating; Metabolic; Metabolism; Mission; Molecular Genetics; Nutrient; Nutrient availability; Nutritional; Oxygen; Pathogenesis; Pathway interactions; Play; Potential Energy; Process; Production; Regulation; Regulator Genes; Reproduction spores; Research; Resistance; Role; Signal Transduction; System; Testing; Toxin; United States National Institutes of Health; Virulence; Work; bile salts; design; diarrheal disease; enteric pathogen; experience; experimental study; genetic approach; in vivo; innovation; nutrient deprivation; nutrition; pathogen; pathogenic bacteria; preference; prevent; rational design; response; transmission process

Project Summary/Abstract Clostridioides difficile (formerly Clostridium) is a major nosocomial pathogen that causes severe diarrheal disease that is highly infectious and difficult to treat. C. difficile is easily transmitted due to the formation and expulsion of up to 108 spores/ml of stool from infected hosts. The spore form of C. difficile is resistant to most disinfectants and is critical for the survival of the bacterium outside of the host intestine. Unfortunately, little is known about the intestinal signals that lead to spore formation. The long-term goal of this investigation is to uncover how nutrition drives C. difficile pathogenesis and transmission. The specific objectives of this application are to determine which distinct nutritional pathways and effectors have the greatest impact on spore production, and how these effects are regulated. Based on our data, we hypothesize that specific intestinal metabolites promote toxin expression and spore formation, while other metabolites impede these processes. The rationale underlying these studies is that uncovering the nutritional cues that drive the production of spores will help us understand how disease and transmission occur. In our preliminary studies, we identified specific nutrients that have dramatic effects on C. difficile spore formation. Capitalizing on our previous experiences in C. difficile molecular genetics, metabolic gene regulation, and Gram-positive intestinal pathogenesis, we will meet the objectives through the experiments detailed in two specific aims. To begin, we will define the specific pathways affected by these compounds and then evaluate the impact of influential nutrients on C. difficile spore formation and transmission. In parallel, we will dissect the regulatory mechanisms that link specific nutrients to spore formation. This research is innovative because it takes advantage of the latest information about the intestinal environment that supports CDI, and combines biochemical and genetic approaches to answer fundamental questions about this important and complex biological process. The expected contribution of this research is a detailed understanding of the relevant bacterial pathways that enable C. difficile sporulation in response to specific nutrients. Moreover, this work is an essential step in the development of rational strategies to impede C. difficile transmission by preventing the formation of infectious spores in the host.

项目概要/摘要 艰难梭菌（以前称为梭状芽胞杆菌）是一种主要的院内病原体，可导致严重腹泻 传染性强且难以治疗的疾病。艰难梭菌由于其形成和传播而很容易传播 从受感染宿主的粪便中排出高达 108 个孢子/毫升。艰难梭菌的孢子形式对大多数细菌都有抵抗力 消毒剂，对于宿主肠道外细菌的生存至关重要。不幸的是，很少有 了解导致孢子形成的肠道信号。本次调查的长期目标是 揭示营养如何驱动艰难梭菌的发病机制和传播。本次活动的具体目标 应用是确定哪些不同的营养途径和效应器对孢子影响最大 生产，以及如何调节这些影响。根据我们的数据，我们假设特定的肠道 代谢物促进毒素表达和孢子形成，而其他代谢物则阻碍这些过程。 这些研究的基本原理是揭示驱动孢子产生的营养线索 将帮助我们了解疾病和传播是如何发生的。在我们的初步研究中，我们确定了具体的 对艰难梭菌孢子形成有显着影响的营养物质。利用我们之前的经验 艰难梭菌分子遗传学、代谢基因调控和革兰氏阳性肠道发病机制，我们将 通过两个具体目标中详细说明的实验来实现目标。首先，我们将定义具体的 受这些化合物影响的途径，然后评估有影响的营养物质对艰难梭菌孢子的影响 形成和传播。与此同时，我们将剖析将特定营养素与 孢子形成。这项研究具有创新性，因为它利用了有关 支持CDI的肠道环境，并结合生化和遗传学方法来回答 关于这一重要而复杂的生物过程的基本问题。本次活动的预期贡献 研究是对艰难梭菌孢子形成的相关细菌途径的详细了解 对特定营养素的反应。此外，这项工作是制定合理策略的重要一步 通过防止宿主中感染性孢子的形成来阻止艰难梭菌的传播。