The Psp response of Yersinia enterocolitica

小肠结肠炎耶尔森氏菌的 Psp 反应

• 批准号: 8215878
• 负责人: ANDREW J. DARWIN
• 金额: $ 45.28万
• 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/8215878
• 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）：耶尔森氏菌属细菌导致多种人类疾病。鼠疫耶尔森氏菌引起臭名昭著的鼠疫疾病，由于其可能被用作生物恐怖主义的媒介，鼠疫已重新引起公众的关注。相反，假结核耶尔森氏菌和小肠结肠炎耶尔森氏菌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菌物种密切相关，并具有一些共同的毒力决定因素。耶尔森氏菌研究为细菌发病机制提供了基本见解，包括广泛传播的三型分泌系统（T3SS）的第一个例子。所有 T3SS 的一个关键成分是一种特殊的外膜成孔蛋白，称为促胰液素。然而，促胰液素的产生会引起细菌细胞包膜应激。这对于小肠结肠炎耶尔森氏菌来说是致命的，除非被称为噬菌体休克蛋白（Psp）系统的关键应激反应发挥作用。因此，小肠结肠炎耶尔森氏菌的 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其核心组件并开始定义它们的作用。我们未来的工作将基于这样的假设：小肠结肠炎耶尔森氏菌 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，并且激活的系统功能可以对抗与细胞质膜相关的问题，例如可能由细胞质膜引起的问题。错误定位的促胰液素。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，通过动态蛋白质-蛋白质相互作用调节 psp 基因表达； (2)分析PspB和PspC蛋白的调节和生理功能，它们在系统中发挥多种重要作用； (3)直接分析小肠结肠炎耶尔森氏菌中促胰液素毒性、促胰液素向细胞质膜的错误定位以及Psp系统功能之间的联系。这些研究除了小肠结肠炎耶尔森氏菌之外还具有广泛的意义，因为对毒力至关重要的含促胰液素系统和 Psp 系统广泛存在于医学上重要的细菌中。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期间发生的应激条件的基本能力。公共卫生相关性：小肠结肠炎耶尔森氏菌会引起人类胃肠炎，并且与鼠疫的病原体鼠疫耶尔森氏菌密切相关。拟议的研究将增加我们对小肠结肠炎耶尔森氏菌应激反应系统的了解，该系统对于其引起疾病的能力至关重要，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至关重要，因为从长远来看，它可能成为设计针对耶尔森氏菌以及其他致病细菌的新治疗策略的目标。