Regulation of Clostridium difficile Colonization Factors

艰难梭菌定植因子的调节

• 批准号: 8810349
• 负责人: RITA TAMAYO
• 金额: $ 1.8万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 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/8810349
• 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; Health; 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' ,5' )-cyclic diguanylic acid; cell motility; cost; factor C; intestinal epithelium; pathogen; prevent

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、专性厌氧菌，可引起从抗生素相关性腹泻到伪膜性结肠炎等多种疾病。近年来，艰难梭菌感染的发病率和严重程度有所增加。然而，人们对发病机制的基本方面的了解却很有限，例如细菌附着在肠上皮上的机制。由于宿主的定植是建立感染的先决条件，因此必须 定义细菌附着到宿主组织的机制，因为这将推动急需的额外治疗和预防方案的发展。该项目的长期目标是了解艰难梭菌如何附着并维持肠上皮的定植。该提案的目的是确定鞭毛和 IV 型菌毛以及控制其产生的机制如何影响艰难梭菌定殖宿主组织的能力。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 型菌毛的生物合成，从而允许它们在定植的适当阶段产生。该假设将通过以下三个具体目标进行检验。具体目标 1 是确定 IV 型菌毛的作用以及 c-di-GMP 对肠道定植和毒力的调节。具体目标 2 是确定 c-di-GMP 如何调节鞭毛基因以及调节如何影响毒力。具体目标 3 是确定感染过程中 IV 型菌毛和鞭毛产生的空间和时间模式，以及协调这些表面细胞器的产生对艰难梭菌定植宿主并引起疾病的能力的重要性。该提案代表了理解艰难梭菌疾病的一个全新的研究领域：控制艰难梭菌定植因子的细胞内信号通路。通过定义法规和 鞭毛和 IV 型菌毛的功能，这些研究将显着扩展我们的知识 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。