Regulation of Clostridium difficile Colonization Factors

艰难梭菌定植因子的调节

基本信息

批准号：
8561260
负责人：
RITA TAMAYO
金额：
$ 30.36万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-20 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8561260
关键词：
Acute Affect Anabolism Anaerobic Bacteria Animal Model Antibiotic Therapy Antibiotics Area Bacteria Caring Cell physiology Cells Clostridium difficile Development Diarrhea Disease Disease Outcome Down-Regulation Fimbriae Proteins Flagella Gene Expression Genes Goals Human Immune Incidence Infection Infection prevention Intestines Investigation Knowledge Large Intestine Mission Mutation Operon Organelles Pathogenesis Pattern Pilum Prevention Production Pseudomembranous Colitis Recurrence Regulation Regulatory Pathway Research Role Severities Signal Pathway Signaling Molecule Staging Structure Surface System Testing Tissues Toxin United States United States National Institutes of Health Virulence Work bis(3&apos ,5&apos )-cyclic diguanylic acid cell motility cost factor C intestinal epithelium pathogen prevent public health relevance

项目摘要

DESCRIPTION (provided by applicant): Clostridium difficile is a Gram-positive, obligate anaerobe that causes diseases ranging from antibiotic- associated diarrhea to pseudomembranous colitis. In recent years, the incidence and severity of C. difficile infections has increased. Yet there is only limited knowledge of fundamental aspects of pathogenesis, such as the mechanisms used by the bacterium to attach to the intestinal epithelium. Because colonization of the host is a prerequisite for establishing an infection, it is imperative that the mechanisms underlying bacterial attachment to host tissues be defined, as this will drive the much-needed development of additional treatment and prevention options. The long-term goal of this project is to understand how C. difficile attaches to and maintains colonization of the intestinal epithelium. The objective of this proposal is to determine how flagella and Type IV pili as well as the mechanisms controlling their production, impact the ability of C. difficile to colonize host tissues. The central hypothesis of this study is that the bacterial signaling molecule c-di-GMP oppositely regulates the biosynthesis of flagella and Type IV pili, allowing their production at appropriate stages of colonization. This hypothesis will be tested with the following three specific aims. Specific aim 1 is to determine the effect of the Type IV pilus and is regulation by c-di-GMP on intestinal colonization and virulence. Specific aim 2 is to determine how flagellar genes are regulated by c-di-GMP and how regulation affects virulence. Specific aim 3 is to determine the spatial and temporal patterns of Type IV pilus and flagellum production during infection and the importance of coordinating production of these surface organelles on the ability of C. difficile to colonize the host and cause disease. This proposal represents an entirely new area of investigation toward understanding C. difficile disease: the intracellular signaling pathways controlling colonization factors of C. difficile. By defining the regulation and function of flagella and Type IV pili, these studies will significantly expand our knowledge of how C. difficile controls colonization of the host and may reveal targets for inhibition of intestinal colonization to thereby prevent disease.

描述（由申请人提供）：艰难梭菌是一种革兰氏阳性的，强性的厌氧菌，导致疾病从抗生素相关的腹泻到假膜性结肠炎。近年来，艰难梭菌感染的发病率和严重程度增加了。然而，只有对发病机理的基本方面的知识有限，例如细菌用来附着在肠上皮上的机制。因为宿主的殖民化是建立感染的先决条件，所以必须定义了细菌附着在宿主组织上的机制，因为这将推动急需的额外治疗和预防选择的发展。该项目的长期目标是了解艰难梭菌如何与肠上皮的定殖并保持定植。该提案的目的是确定鞭毛和IV型Pili以及控制其产量的机制，影响艰难梭菌在宿主组织定殖的能力。这项研究的中心假设是细菌信号分子C-DI-GMP相反地调节鞭毛和IV型Pili的生物合成，从而使其在适当的定殖阶段产生。该假设将通过以下三个特定目标进行检验。具体目的1是确定IV型菌毛的影响，并通过C-DI-GMP调节对肠道定殖和毒力。具体目的2是确定鞭毛基因如何受C-DI-GMP调节以及调节如何影响毒力。具体目的3是确定感染过程中IV孢子和鞭毛产生的空间和时间模式，以及将这些表面细胞器的生产在艰难梭菌在宿主定居并引起疾病的能力上的重要性。该提案代表了针对理解艰难梭菌疾病的一个全新的调查领域：控制艰难梭菌定植因子的细胞内信号传导途径。通过定义法规和鞭毛和IV型Pili的功能，这些研究将大大扩展我们对如何艰难梭菌控制宿主的定植，并可能揭示抑制肠道定植的靶标，从而预防疾病。