Type III Secretion in Bordetella

描述(申请人提供)：波尔德氏菌属包括几个密切相关的革兰氏阴性细菌亚种，它们在哺乳动物的纤毛呼吸道上皮表面定居。除了它们作为感染源的重要性外，波氏杆菌属的成员还为探测细菌与宿主的相互作用提供了极好的模型。具有不同寄主适应性的高度相关亚种的可用性使发病机制的比较研究成为可能。尽管百日咳杆菌只适应于人类，但支气管败血杆菌的宿主范围非常广泛，包括各种实验动物。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致病的分子基础。 我们已经在败血杆菌中发现了一种III型分泌系统(TTSS)，它似乎在促进呼吸道上皮持续感染方面发挥了关键作用。最近的研究结果表明，百日咳杆菌的III型分泌器基因、调节基因和分泌蛋白编码基因被活跃地转录。此外，控制TTS的BTRS监管系统已经存在并发挥了作用。这项建议的目的是对波尔德氏菌亚种的TTS进行全面的比较分析，该亚种对人类和其他动物具有传染性。我们的研究结果将有助于从根本上理解细菌毒力的致病机制和进化。具体来说，我们建议： 1.对波尔德氏菌亚种的BTRs基因进行了比较分析。BTRs是一种新发现的西格玛因子，它位于复杂的调控体系的顶端，控制着III型分泌基因和其他基因的表达。这些研究有可能发现新的毒力因子和调控机制。 2.确定“伴侣切换子”同系物在调节III型分泌中的作用。伴侣交换代表了细菌调控的一种新的、不断扩大的范例。我们将检验这一假设，即BtrU，V，W伙伴转换复合体的行为差异解释了波氏杆菌亚种之间在控制III型分泌方面的差异。 3.研究百日咳杆菌和败血杆菌在呼吸道感染过程中III型分泌物和其他BTRS调节表型的影响。

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.