Type III Secretion in Bordetella

描述（由申请方提供）：博德特氏菌属包括几个密切相关的革兰氏阴性菌亚种，它们在哺乳动物的纤毛呼吸道上皮表面定植。除了它们作为感染因子的重要性之外，博德特氏菌属的成员还为探测细菌-宿主相互作用提供了极好的模型。具有不同宿主适应性的高度相关亚种的可用性允许对发病机制进行比较研究。虽然B.百日咳只适合人类，B。支气管败血症具有非常广泛的宿主范围，包括各种实验室动物。B。支气管败血症模型允许在自然宿主-寄生虫相互作用的背景下评估发病机制的分子基础。 我们在B中发现了一个III型分泌系统（TTSS）。支气管败血症，似乎在促进呼吸道上皮的持续感染中起关键作用。最近的研究结果表明，III型分泌（TTS）装置基因，调节基因，和编码分泌蛋白的基因在B中被积极转录。百日咳。此外，控制TTS的BtrS调节系统存在并发挥作用。本提案的目的是对感染人类和其他动物的博德特氏菌亚种进行全面的TTS比较分析。我们的研究结果将有助于从根本上了解致病机制和细菌毒力的演变。具体而言，我们建议： 1.对博德特氏菌亚种中的BtrS调节子进行比较分析。BtrS是一种新发现的sigma因子，位于控制III型分泌位点和其他基因表达的复杂调控层级的顶部。这些研究有可能发现新的毒力因子和调控机制。 2.确定“伴侣转换器”同源物在III型分泌调节中的作用。伴侣转换代表了细菌调控中一种新的和不断扩展的范式。我们将检验以下假设：BtrU、V、W伴侣转换复合物的行为差异导致博德特氏菌亚种之间III型分泌控制的差异。 3.研究B在呼吸道感染过程中III型分泌和其他BtrS调节表型的作用。百日咳和B.支气管炎

DESCRIPTION (provided by applicant): The Bordetella genus includes several closely related subspecies of Gram-negative bacteria that colonize ciliated respiratory epithelial surfaces in mammals. In addition to their importance as infectious agents, members of the Bordetella genus provide excellent models for probing bacterial-host interactions. The availability of highly related subspecies with different host adaptations allows comparative studies of pathogenesis. Although B. pertussis is exclusively adapted to humans, B. bronchiseptica has a remarkably broad host range that includes a variety of laboratory animals. B. bronchiseptica models allow assessments of the molecular basis of pathogenesis in the context of natural host-parasite interactions. We have identified a type III secretion system (TTSS) in B. bronchiseptica that appears to play a key role in facilitating persistent infection of the respiratory epithelium. Recent results indicate that type III secretion (TTS) apparatus genes, regulatory genes, and genes encoding secreted proteins are actively transcribed in B. pertussis. Furthermore, the BtrS regulatory system that controls TTS is present and functional. The objective of this proposal is to conduct a comprehensive comparative analysis of TTS in Bordetella subspecies infectious for humans and other animals. Results from our studies will contribute to a fundamental understanding of mechanisms of pathogenesis and the evolution of bacterial virulence. Specifically, we propose to: 1. Conduct a comparative analysis of the BtrS regulons in Bordetella subspecies. BtrS is a newly identified sigma factor that sits at the top of a complex regulatory hierarchy controlling expression of type III secretion loci and other genes. These studies have the potential to discover novel virulence factors and regulatory mechanisms. 2. Determine the roles of "partner switcher" homologs in the regulation of type III secretion. Partner switching represents a new and expanding paradigm in bacterial regulation. We will test the hypothesis that differences in the behavior of the BtrU,V,W partner switching complex accounts for differences in the control of type III secretion between Bordetella subspecies. 3. Investigate the effects of type III secretion and other BtrS-regulated phenotypes during respiratory tract infection by B. pertussis and B. bronchiseptica.