Campylbacter jejuni flagellar regulation and synthesis

描述（由申请人提供）：空肠弯曲杆菌是美国和世界其他国家人类肠胃炎的主要原因。根据疾病控制中心的数据，空肠梭菌与沙门氏菌是导致美国细菌性肠胃炎的主要原因。相比之下，空肠梭菌是野生和农业重要动物胃肠道的常见共生生物，这有助于在人类食物供应中发现大量空肠梭菌，导致散发的疾病病例。鞭毛运动是空肠梭菌唯一被证实的毒力和定植因子，是促进人类和鸟类感染以发展疾病或共生所必需的。空肠梭菌在细菌的一个或两个极点产生一个鞭毛。因此，空肠假单胞菌属于一组重要的细菌病原体，如弧菌、假单胞菌和幽门螺杆菌，它们被编程为产生有限数量的鞭毛，并将这些细胞器放置在极点，不像大肠杆菌和沙门氏菌等更常见的周围细菌。我们以空肠梭菌为模型系统来了解鞭毛基因在极鞭毛细菌病原体中的表达和生物合成调控。该调控系统需要鞭毛输出装置、FlgSR双组分系统和FlhF GTPase来表达c54依赖性鞭毛基因。此外，FlhF和假定的ATP结合蛋白FlhG对于鞭毛的适当放置、数量或生物合成是必需的，FlhG在分离中具有额外的功能。本研究的目的是分析空肠梭菌中介导鞭毛基因正确表达的信号过程，同时利用鞭毛调控系统促进对信号网络、复杂细胞器发育和细菌分离的细胞生物学的更深入理解。在Aim 1中，我们将分析发生在鞭毛输出装置和FlgS传感器激酶之间的一种新的信号传导机制，该机制导致FlgSR系统的激活。在Aim 2中，我们将分析FlgR的生物学，FlgR是一种ntrc样蛋白，它包含一个独特的C末端，允许信号转导和转录起始的可能替代机制。在Aim 3中，我们将分析FlhF如何影响鞭毛基因的表达和生物合成，以及FlhF在控制极性鞭毛数量和分离方面的双重功能。这些目标的实现将有助于理解：1)细菌中蛋白质系统之间信号传导的独特分子机制；2) ntrc样蛋白转录起始的替代机制；3)细菌中的信号网络如何相互隔离以介导信号的特异性；4)复杂细胞器发育；5)细菌分离方面。

DESCRIPTION (provided by applicant): Campylobacter jejuni is a leading cause of gastroenteritis in humans in the United States and in other countries throughout the world. According to the Centers for Disease Control, C. jejuni competes with Salmonella species as the leading cause of bacterial gastroenteritis in the United States. In contrast, C. jejuni is a common commensal organism of the gastrointestinal tracts of wild and agriculturally-important animals, which contributes to the large amount of C. jejuni found in the human food supply leading to sporadic cases of disease. Flagellar motility is the only proven virulence and colonization factor of C. jejuni, required to promote infection of humans and avian species for the development of disease or commensalism. C. jejuni produces a single flagellum at one or both poles of the bacterium. Thus, C. jejuni belongs to a significant group of bacterial pathogens, such as Vibrio, Pseudomonas, and Helicobacter species, that are programmed to produce a limited number of flagella and place these organelles only at the poles, unlike more commonly studied peritrichous bacteria such as E. coli and Salmonella species. We have used C. jejuni as a model system to understand regulation of flagellar gene expression and biosynthesis in polarly-flagellated bacterial pathogens. This regulatory system requires the flagellar export apparatus, the FlgSR two-component system and the FlhF GTPase for expression C54-dependent flagellar genes. In addition, FlhF and the putative ATP- binding protein, FlhG, are required for proper flagellar placement, number, or biosynthesis with FlhG possessing an additional function in septation. The objectives of this proposal are to analyze signaling processes in C. jejuni that mediate proper expression of flagellar genes while using the flagellar regulatory system to promote a deeper understanding into the cellular biology of signaling networks, complex organelle development, and bacterial septation. In Aim 1, we will analyze a novel signaling mechanism occurring between the flagellar export apparatus and the FlgS sensor kinase that leads to activation of the FlgSR system. In Aim 2, we will analyze the biology of FlgR, an NtrC-like protein, which contains a unique C- terminus that allows for a likely alternative mechanism of signal transduction and transcriptional initiation. In Aim 3, we will analyze how FlhF influences flagellar gene expression and biosynthesis and the dual functions of FlhG in controlling polar flagellar number and septation. Accomplishment of these aims will aid in understanding: 1) a unique molecular mechanism of signaling between protein systems in bacteria; 2) alternative mechanisms of transcriptional initiation for an NtrC-like protein; 3) how signaling networks in bacteria are insulated from each other to mediate specificity of signaling; 4) complex organelle development; and 5) aspects of bacterial septation. PUBLIC HEALTH RELEVANCE: Campylobacter jejuni produces a flagellum that is required for motility, infection of humans to promote diarrheal disease, and infection of animals to promote colonization. The proposed research will examine how regulatory proteins of C. jejuni function together to control production of flagella and influence other aspects of cellular biology such as bacterial division. By accomplishing research proposed in this work, we may reveal new steps in the production of virulence and colonization factors required by bacteria to promote infection that could be targeted for inactivation by therapeutics.