A periplasmic global regulator, ExoR, for bacterial invasion of host cells

细菌入侵宿主细胞的周质全局调节因子 ExoR

• 批准号: 7941499
• 负责人: HAI-PING CHENG
• 金额: $ 12.23万
• 依托单位: HERBERT H. LEHMAN COLLEGE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7941499
• 关键词: Animals; Antibiotics; Applications Grants; Area; B-Lymphocytes; Bacteria; Bacterial Adhesion; Bacterial Infections; Bacterial Proteins; Bacteriology; Binding; Biochemical; Biological Models; Biological Process; Brucella abortus; Brucella abortus infection; C-terminal; Cells; Collaborations; Congresses; Costa Rica; Data; Development; Educational process of instructing; Engineering; Environmental Microbiology; Feedback; Figs - dietary; Flagella; Foundations; Fox Chase Cancer Center; Funding; Gene Expression; Grant; Grant Review; Hair Cells; Health; Homeostasis; Homologous Gene; Implant; Indiana; Institution; International; Invaded; Journals; Lead; Life; Life Style; Manuscripts; Mediating; Medical Device; Melilotus; Membrane; Microbe; Minor; Modeling; Molecular; Molecular Biology; Multi-Drug Resistance; Nitrogen Fixation; Paper; Pathogenicity; Peptide Hydrolases; Periplasmic Proteins; Philadelphia; Plant Roots; Plants; Polysaccharides; Positioning Attribute; Preparation; Production; Productivity; Proteins; Proteolysis; Publications; Publishing; Regulation; Regulation of Proteolysis; Regulatory Pathway; Reporting; Research; Research Project Grants; Research Support; Rhizobium radiobacter; Role; Signal Transduction; Sinorhizobium meliloti; Site; Sodium Chloride; Solid; Stimulus; Structure; Students; Suggestion; Surface; Symbiosis; System; Testing; Time; Training; United States National Institutes of Health; Universities; Virulence Factors; Visit; Writing; base; career; cell motility; clay; environmental change; improved; novel strategies; pathogen; pathogenic bacteria; periplasm; programs; public health relevance; research and development; response; sensor; skills; succinoglycan; symposium

DESCRIPTION (provided by applicant): Bacterial infections and surface colonization of implanted medical devices are and will continue to be major health threats especially with the development of multiple drug resistant pathogens. Bacterial pathogens rely on their membrane sensors to detect the presence of host cells in order to produce virulence factors at the right time to invade host cells or colonize the surface of medical devices. Blocking bacterial sensing of hosts could be a new approach to stop bacterial infection. As part of our long term effort to understand bacterial sensing and signaling during host cell invasion, we are studying the molecular mechanism of Sinorhizobium meliloti ExoR protein in controlling the switch from free living cells to invasion ready cells. We have shown previously that both the ExoR protein and the ExoS/ChvI two-component regulatory system regulates inversely the production of a polysaccharide (succinoglycan) required for host cell invasion, and flagella, required for bacterial motility. Our current hypothesis is that the active form of the ExoR protein (ExoRm) binds ExoS and keeps it in the OFF state, altering the expression of the genes regulated by ExoS/ChvI system. The amount of ExoRm in the periplasm is maintained through feedback regulation and the proteolysis of ExoRm to produce ExoRc20. The changes in ExoRm proteolysis rate is being used by the cells to sense environmental stimuli control the switch between free living and attached living. This model is based on the following key discoveries made in the last two years. First, ExoR functions upstream of ExoS/ChvI two-component regulatory system and negatively regulates the activity of ExoS; Second, ExoR autoregulates through feedback regulation; Third, ExoR is digested in periplasm to generate ExoRc20. We plan to 1) determine the function of different forms of ExoR proteins by expressing different forms of ExoR, ExoRp, ExoRm, and ExoRc20, individually; and by examining their biological functions and their ability to interact directly with ExoS protein; 2) determine the molecular mechanisms of ExoR proteolysis and its regulation by characterizing the molecular mechanism of ExoR proteolysis; identifying environmental stimuli modulating ExoR proteolysis, and identifying the S. meliloti ExoR protease. Our new discoveries can be applied immediately to the understanding of the pathogenicities of 56 animal and plant pathogens that have close homologs of S. meliloti ExoR. Our new discoveries will contribute to the development of new approaches to control bacterial infections. PUBLIC HEALTH RELEVANCE: After sensing the presence of their hosts, most pathogenic bacteria produce special products to enhance their abilities to infect host cells. Our study will lead to the development of new approaches to control bacterial infections by blocking their abilities to sense of the presence of their hosts.

描述（由申请人提供）：植入医疗器械的细菌感染和表面定植现在并将继续成为主要的健康威胁，特别是随着多种耐药病原体的发展。细菌病原体依靠其膜传感器来检测宿主细胞的存在，以便在正确的时间产生毒力因子来侵入宿主细胞或定殖在医疗设备的表面。阻断宿主的细菌感应可能是阻止细菌感染的新方法。作为我们了解宿主细胞入侵过程中细菌传感和信号传导的长期努力的一部分，我们正在研究苜蓿中华根瘤菌 ExoR 蛋白控制从游离活细胞向入侵就绪细胞转变的分子机制。我们之前已经证明，ExoR 蛋白和 ExoS/ChvI 双组分调节系统反向调节宿主细胞侵袭所需的多糖（琥珀酸聚糖）和细菌运动所需的鞭毛的产生。我们目前的假设是，ExoR 蛋白 (ExoRm) 的活性形式结合 ExoS 并将其保持在 OFF 状态，从而改变 ExoS/ChvI 系统调控的基因的表达。通过反馈调节和 ExoRm 的蛋白水解产生 ExoRc20 来维持周质中 ExoRm 的量。细胞利用 ExoRm 蛋白水解率的变化来感知环境刺激，控制自由生活和附着生活之间的转换。该模型基于过去两年的以下重要发现。首先，ExoR在ExoS/ChvI双组分调控系统上游发挥作用，负向调节ExoS的活性；其次，ExoR通过反馈调节进行自动调节；第三，ExoR在周质中被消化生成ExoRc20。我们计划1）通过分别表达不同形式的ExoR、ExoRp、ExoRm和ExoRc20来确定不同形式ExoR蛋白的功能；并通过检查它们的生物学功能以及它们与 ExoS 蛋白直接相互作用的能力； 2）通过表征ExoR蛋白水解的分子机制，确定ExoR蛋白水解的分子机制及其调控；识别调节 ExoR 蛋白水解的环境刺激，并识别苜蓿中华根瘤菌 ExoR 蛋白酶。我们的新发现可以立即应用于了解与苜蓿中华根瘤菌 ExoR 具有密切同源性的 56 种动植物病原体的致病性。我们的新发现将有助于开发控制细菌感染的新方法。 公共卫生相关性：大多数病原菌在感知到宿主的存在后，会产生特殊的产物来增强其感染宿主细胞的能力。我们的研究将导致开发新方法，通过阻止细菌感知宿主存在的能力来控制细菌感染。