Mechanisms Underlying Nutrient-Mediated Sporulation in C. difficile

项目总结/摘要 艰难梭菌（Clostridioides difficile）（以前称为梭菌属）是引起严重腹泻的主要院内病原体 传染性强且难以治疗的疾病。艰难梭菌由于形成而容易传播， 从受感染的宿主排出高达108个孢子/ml的粪便。C.艰难梭菌对大多数 消毒剂，并且对于细菌在宿主肠外的存活至关重要。不幸的是， 了解导致孢子形成的肠道信号。这项调查的长期目标是 揭示营养如何驱动C。发病机制和传播途径。这一具体目标 应用是确定哪些不同的营养途径和效应器对孢子的影响最大 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，我们确定了特定的 对C.难以形成孢子。利用我们以前在 C.艰难的分子遗传学，代谢基因调控，和革兰氏阳性肠道发病机制，我们将 通过在两个具体目标中详述的实验来实现这些目标。开始，我们将定义特定的 途径受这些化合物的影响，然后评估有影响的营养素对C。艰难梭菌抱子 形成和传播。与此同时，我们将剖析将特定营养素与 孢子形成这项研究是创新的，因为它利用了有关 肠道环境，支持CDI，并结合生物化学和遗传学的方法来回答 这一重要而复杂的生物学过程的基本问题。这一预期贡献 研究是详细了解相关的细菌途径，使C。艰难孢子形成 对特定营养素的反应。此外，这项工作是制定合理战略的必要步骤 阻碍C.通过阻止感染性孢子在宿主体内的形成而难以传播。

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.