The Psp response of Yersinia enterocolitica

描述（由申请人提供）：耶尔森氏菌属细菌是多种人类疾病的罪魁祸首。鼠疫耶尔森氏菌引起黑死病，由于其作为生物恐怖主义制剂的潜在用途，最近在公众意识中重新获得突出地位。相反，假结核杆菌和小肠结肠炎杆菌主要引起胃肠道疾病。然而，尽管疾病症状不同，这三种致病性耶尔森菌密切相关，并有几个共同的毒力决定因素。耶尔森菌的研究为细菌的发病机制提供了基本的见解，包括广泛存在的III型分泌系统（TTSS）的第一个例子。与所有细菌性病原体一样，在耶尔森氏菌中，许多在毒力中起重要作用的蛋白质，包括TTSS的成分，都位于细胞包膜中。在某些条件下，一些包膜蛋白会发生错误折叠/错误定位。特定的应激反应机制处理这个问题，其中的例子是大肠杆菌和相关生物的RpoE和Cpx系统。这些胞质外应激反应在宿主感染过程中起重要作用。该建议的中心假设是，小肠结肠炎Y.噬菌体-冲击蛋白位点（psp）编码了一个不同的胞质外应激反应系统。小肠结肠炎芽孢杆菌突变体是无毒的，在其他细菌病原体中也发现了同源的芽孢杆菌位点，包括鼠疫杆菌和霍乱弧菌。我们的初步数据表明，Psp系统对几种与毒力有关的包膜蛋白的错误定位有反应，包括至少一种TTSS成分。通过研究Psp系统，我们将进一步了解细菌在宿主感染过程中对应激条件作出反应的基本能力。具体而言，我们建议：(1)分析诱导Psp系统的蛋白质，并表征Psp诱导剂与RpoE/Cpx诱导剂之间的任何重叠；(2)确定Psp系统的拓扑结构，并研究Psp如何允许胞质外应激通过细胞质膜被感知和发出信号；(3)对Psp系统直接控制的基因进行表征，以进一步确定胁迫应答成分。

DESCRIPTION (provided by applicant): Bacteria of the genus Yersinia are responsible for a variety of human diseases. Y. pestis causes Bubonic Plague, and has recently regained prominence in public awareness due to its potential use as an agent of bioterrorism. In contrast, Y. pseudotuberculosis and Y. enterocolitica cause primarily gastrointestinal disease. However, despite the differences in disease symptoms, the three pathogenic Yersinia species are closely related, and share several common virulence determinants. Yersinia studies have provided fundamental insights into bacterial pathogenesis, including the first example of the widespread type III secretion system (TTSS). In Yersinia, as in all bacterial pathogens, many of the proteins that play important roles in virulence, including components of the TTSS, are located in the cell envelope. Under certain conditions, some envelope proteins become misfolded/mislocalized. Specific stress-response mechanisms deal with this problem, examples of which are the RpoE and Cpx systems of Escherichia coli and related organisms. These extracytoplasmic stress responses play important roles during host infection. The central hypothesis of this proposal is that a different extracytoplasmic stress response system is encoded by the phage-shock-protein locus (psp) of Y. enterocolitica. A Y. enterocolitica psp mutant is avirulent, and homologus psp loci are found in other bacterial pathogens, including Y. pestis and Vibrio cholerae. Our preliminary data indicate that the Psp system responds to mislocalization of several envelope proteins involved in virulence, including at least one component of a TTSS. By studying the Psp system we will gain further insight into the essential ability of bacteria to respond to stressful conditions that occur during host infection. Specifically, we propose to: (1) Analyze the proteins that induce the Psp system and characterize any overlap between Psp inducers and RpoE/Cpx inducers; (2) Determine the topology of the Psp system, and investigate how Psp allows extracytoplasmic stress to be sensed and signaled across the cytoplasmic membrane; (3) Characterize genes directly controlled by the Psp system, in order to identify further stress response components.