Regulation of Clostridium difficile Colonization Factors

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假膜性结肠炎等疾病。近年来，艰难梭菌感染的发生率和严重程度有所增加。然而，对发病机制的基本方面，如细菌附着于肠上皮的机制，了解有限。由于寄主的定植是建立感染的先决条件，因此必须使寄主在感染前

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.