The Psp response of Yersinia enterocolitica

描述(申请人提供)：耶尔森氏菌属细菌导致多种人类疾病。鼠疫杆菌引起鼠疫，最近由于它可能被用作生物恐怖主义的媒介而重新引起公众的注意。相比之下，假结核和小肠结肠炎耶尔森菌主要引起胃肠道疾病。然而，尽管疾病症状不同，但这三个致病耶尔森氏菌物种之间关系密切，并拥有几个共同的毒力决定因素。耶尔森氏菌的研究为细菌的发病机制提供了基本的见解，包括第一个广泛存在的III型分泌系统(TTSS)的例子。在耶尔森氏菌中，就像在所有细菌病原体中一样，许多在毒力方面发挥重要作用的蛋白质，包括TTSS的成分，都位于细胞膜中。在某些条件下，一些包膜蛋白会发生错误折叠/错位。特定的应激反应机制解决了这个问题，例如大肠杆菌和相关生物体的RpoE和CPx系统。这些胞外应激反应在宿主感染过程中起着重要作用。这一建议的中心假设是，小肠结肠炎耶尔森菌的噬菌体-休克-蛋白位点(PSP)编码了一种不同的胞外应激反应系统。小肠结肠炎耶尔森菌PSP突变体是无毒的，在其他细菌病原体中也发现了同源的PSP基因座，包括鼠疫杆菌和霍乱弧菌。我们的初步数据表明，PSP系统对几个与毒力有关的包膜蛋白的错误定位做出反应，包括TTSS的至少一个成分。通过研究PSP系统，我们将进一步了解细菌对宿主感染期间发生的应激条件做出反应的基本能力。具体地说，我们建议：(1)分析诱导PSP系统的蛋白质，并表征PSP诱导子和RpoE/CPX诱导子之间的任何重叠；(2)确定PSP系统的拓扑结构，并研究PSP如何允许胞外胁迫通过细胞膜进行感知和信号传递；(3)表征PSP系统直接控制的基因，以确定进一步的胁迫反应成分。

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.