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）：耶尔森氏菌属细菌是多种人类疾病的致病菌。Y.鼠疫引起臭名昭著的疾病鼠疫，由于其作为生物恐怖主义的潜在用途，鼠疫在公众意识中重新获得突出地位。相比之下，Y. pseudotuberculosis和Y.小肠结肠炎主要引起胃肠道疾病。然而，尽管疾病症状不同，但这三种致病性耶尔森氏菌物种密切相关，并共享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，包括广泛分布的第三型分泌系统（T3 SS）的第一个例子。所有T3 SS的一个关键组成部分是一种专门的外膜孔形成蛋白，称为分泌素。然而，分泌素的产生可引起细菌细胞被膜应激。这对Y来说是致命的。除非称为噬菌体休克蛋白（Psp）系统的关键应激反应是功能性的，否则小肠结肠炎。因此，Y.小肠结肠炎菌是其毒力所必需的。迄今为止，我们对PSP系统的研究已经确定了其核心组件，并开始定义它们的作用。我们今后的工作将基于以下假设：小肠结肠炎Psp系统由复杂和动态的蛋白质-蛋白质相互作用介导，并且激活的系统起作用以对抗与细胞质膜相关的问题，例如可能由错误定位的分泌素引起的问题。为了解决这些假设，我们提出：（1）测试PspFABC蛋白如何通过动态蛋白质-蛋白质相互作用构成调节psp基因表达的信号转导系统的各种模型：（2）分析PspB和PspC蛋白的调节和生理功能，它们在该系统中发挥多种重要作用;（3）直接分析分泌素的毒性、分泌素在细胞膜上的错误定位以及Psp系统功能之间的关系。小肠结肠炎这些研究在Y.小肠结肠炎是因为含有分泌素的系统和Psp系统对于毒力至关重要，在医学上重要的细菌中广泛存在。因此，通过了解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。公共卫生相关性：小肠结肠炎耶尔森氏菌引起人类胃肠炎，与鼠疫耶尔森氏菌密切相关。鼠疫这项研究将增加我们对Y.小肠结肠炎是其致病能力所必需的，并且也存在于许多其他医学上重要的细菌中。了解这种应激反应系统是至关重要的，因为从长远来看，它可能是设计针对耶尔森氏菌和其他致病细菌的新治疗策略的目标。