The Psp response of Yersinia enterocolitica

小肠结肠炎耶尔森氏菌的 Psp 反应

• 批准号: 8241198
• 负责人: ANDREW J. DARWIN
• 金额: $ 6.83万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8241198
• 关键词: Address; Affect; Area; Attention; Awareness; Bacteria; Bacteriophages; Biochemical; Bioterrorism; Cell Fractionation; Cell Membrane Permeability; Cell membrane; Complex; Cytoplasmic Tail; Disease; Escherichia coli; Future; Gastroenteritis; Gastrointestinal Diseases; Gene Expression; Genes; Health; Heart; Human; Immunoblotting; In Vitro; Infection; Integral Membrane Protein; Investigation; Laboratories; Link; Location; Mediating; Membrane; Membrane Potentials; Modeling; Mus; Pasteurella pseudotuberculosis; Pathogenesis; Physiological; Plague; Play; Positioning Attribute; Production; Proteins; Proton-Motive Force; Regulation; Research; Role; Secretin; Shock; Signal Transduction; Signal Transduction Pathway; Site-Directed Mutagenesis; Stress; Symptoms; System; Testing; Toxic effect; Transcription Coactivator; Translating; Transmembrane Domain; Virulence; Work; Yersinia; Yersinia enterocolitica; Yersinia pestis; base; biological adaptation to stress; cell envelope; design; follow-up; human disease; insight; mutant; novel therapeutics; porin; prevent; protein protein interaction; response; yeast two hybrid system

DESCRIPTION (provided by applicant): Bacteria of the genus Yersinia are responsible for a variety of human diseases. Y. pestis causes the infamous disease Plague, which has 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, these 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 three secretion system (T3SS). A critical component of all T3SSs is a specialized outer membrane pore-forming protein known as a secretin. However, secretin production can cause bacterial cell envelope stress. This is lethal to Y. enterocolitica unless a critical stress response known as the phage-shock-protein (Psp) system is functional. As a result, the Psp system of Y. enterocolitica is essential for its virulence. Our studies on the Psp system to date have identified its core components and begun to define their roles. We will base our future work on the hypotheses that regulation of the Y. enterocolitica Psp system is mediated by complex and dynamic protein- protein interactions, and that the activated system functions to counter problems associated with the cytoplasmic membrane, such as can be caused by a mislocalized secretin. To address these hypotheses we propose to: (1) Test various models of how the PspFABC proteins may constitute a signal transduction system that regulates psp gene expression via dynamic protein-protein interactions; (2) Analyze the regulatory and physiological functions of the PspB and PspC proteins, which play multiple essential roles in the system; (3) Directly analyze the connections between secretin toxicity, secretin mislocalization to the cytoplasmic membrane, and the function of the Psp system in Y. enterocolitica. These studies also have broad significance beyond Y. enterocolitica because secretin-containing systems critical for virulence, and the Psp system, are widespread in medically important bacteria. Therefore, by understanding the Psp system we will gain further insight into the essential ability of bacteria to respond to stressful conditions that occur during host infection. PUBLIC HEALTH RELEVANCE: The bacterium Yersinia enterocolitica causes human gastroenteritis, and is closely related to the causative agent of Plague, Y. pestis. The proposed research will increase our understanding of a stress-response system in Y. enterocolitica that is essential for its ability to cause disease, and is also present in numerous other medically important bacteria. Understanding this stress-response system is vital, because in the long-term it could be a target for the design of new therapeutic strategies against Yersinia species as well as other disease- causing bacteria.

描述（由申请人提供）：Yersinia属的细菌负责各种人类疾病。 Y. Pestis引起了臭名昭著的疾病鼠疫，由于其潜在用作生物恐怖主义的推动者，该疾病恢复了公众意识。相比之下，Y. pseudotuberculosis和Y.肠结肠炎主要引起胃肠道疾病。然而，尽管疾病症状存在差异，但这三种致病性耶尔森氏菌种类密切相关，并具有几种常见的毒力决定因素。 Yersinia的研究提供了对细菌发病机理的基本见解，包括第三型三型分泌系统（T3SS）的第一个例子。所有T3SS的关键成分是一种专门的外膜孔形成蛋白，称为sectionin。但是，分泌素的产生会导致细菌细胞包膜胁迫。这对小肠肠结肠炎是致命的，除非称为噬菌体 - 蛋白质（PSP）系统的临界应力反应是功能的。结果，小肠结肠炎的PSP系统对于其毒力至关重要。我们迄今为止对PSP系统的研究已经确定了其核心组成部分，并开始定义其角色。我们将在未来的工作基础上基于Y型小肠结肠炎PSP系统的调节的假设，是由复杂和动态蛋白质蛋白相互作用介导的，并且活化的系统功能可抵消与细胞质膜相关的问题，例如可能是由错误的倾位分泌素引起的。为了解决这些假设，我们建议：（1）测试PSPFABC蛋白如何构成信号转导系统的各种模型，该系统通过动态蛋白 - 蛋白质相互作用来调节PSP基因表达； （2）分析PSPB和PSPC蛋白的调节和生理功能，这些功能在系统中起多个重要作用； （3）直接分析秘密蛋白毒性，秘密素定位与细胞质膜之间的连接，以及Y. entocolitica中PSP系统的功能。这些研究在小肠肠结肠膜上也具有广泛的意义，因为对毒力至关重要的分泌素系统和PSP系统在医学上重要的细菌中普遍存在。因此，通过了解PSP系统，我们将进一步了解细菌应对宿主感染过程中发生的压力状况的基本能力。公共卫生相关性：耶尔森氏菌细菌会引起人类胃肠炎，并且与瘟疫的病因密切相关。拟议的研究将提高我们对Y. Enterocolitica中应力反应系统的理解，这对于其引起疾病的能力至关重要，并且也存在于许多其他重要的医学重要细菌中。了解这种应力反应系统至关重要，因为从长远来看，它可能是针对耶尔森氏菌种类以及其他疾病的新治疗策略设计的目标。