The Psp response of Yersinia enterocolitica

小肠结肠炎耶尔森氏菌的 Psp 反应

• 批准号: 8014927
• 负责人: ANDREW J. DARWIN
• 金额: $ 37.38万
• 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/8014927
• 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罪魁祸首。鼠疫杆菌引起臭名昭著的鼠疫，由于它可能被用作生物恐怖主义的一种媒介，它重新引起了公众的重视。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，包括广泛存在的第三型分泌系统（T3SS）的第一个例子。所有t3ss的关键成分是一种特殊的外膜成孔蛋白，称为分泌素。然而，分泌素的产生会引起细菌的细胞膜压力。这对小肠结肠炎致病菌是致命的，除非被称为噬菌体-休克蛋白（Psp）系统的临界应激反应起作用。因此，小肠结肠炎耶氏菌的Psp系统对其毒力至关重要。迄今为止，我们对Psp系统的研究已经确定了它的核心组件，并开始定义它们的角色。我们未来的工作将基于以下假设：小肠结肠炎Y. Psp系统的调节是由复杂和动态的蛋白质-蛋白质相互作用介导的，激活的系统功能可以对抗与细胞质膜相关的问题，如分泌素定位错误引起的问题。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-蛋白相互作用构成调节psp基因表达的信号转导系统的各种模型；(2)分析PspB和PspC蛋白的调控和生理功能，PspB和PspC蛋白在系统中起着多重重要作用；(3)直接分析小肠结肠炎病原菌分泌素毒性、分泌素在细胞质膜错定位与Psp系统功能之间的关系。这些研究也具有广泛的意义，而不仅仅是小肠结肠炎耶尔森菌，因为对毒力至关重要的含分泌素系统和Psp系统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在宿主感染期间对应激条件作出反应的基本能力。公共卫生相关性：小肠结肠炎耶尔森菌引起人类胃肠炎，与鼠疫病原体鼠疫杆菌密切相关。拟议的研究将增加我们对小肠结肠炎耶氏菌的应激反应系统的理解，该系统对其致病能力至关重要，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，它可能成为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。