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是并且将继续是主要的健康威胁，尤其是随着多种耐药性病原体的发展。细菌病原体依靠其膜传感器来检测宿主细胞的存在，以便在适当的时候产生毒力因子，以侵入宿主细胞或定居医用器件的表面。阻断宿主的细菌感应可能是阻止细菌感染的一种新方法。作为我们在宿主细胞侵袭过程中了解细菌感测和信号传导的长期努力的一部分，我们正在研究中西氏菌物Meliloti exor蛋白的分子机制，以控制从自由活细胞转变为侵袭入侵的细胞。我们先前已经表明，exor蛋白和EXOS/CHVI两组分组调节系统都会调节宿主细胞浸润所需的多糖（琥珀酸酯）和细菌运动所需的鞭毛。我们目前的假设是，驱虫蛋白（Exorm）的活性形式结合了EXOS并将其保持在OFF状态，从而改变了由外eSOS/CHVI系统调节的基因的表达。通过反馈调节和EXORS的蛋白水解来维持周期中的EXOR量以产生Exorc20。细胞使用Exorm蛋白水解速率的变化来感知环境刺激控制自​​由生活和附着的生活之间的切换。该模型基于过去两年中以下关键发现。首先，ExoS/CHVI两组分组的调节系统上游的exor函数，并对EXOS的活性进行负调节。其次，Exor通过反馈调节进行自动调节；第三，exor在pariplasm中被消化以产生exorc20。我们计划1）通过单独表达不同形式的exor，Exorp，exorm和exorc20来确定不同形式的Exor蛋白的功能；并检查其生物学功能及其直接与外来蛋白相互作用的能力； 2）通过表征Exor蛋白水解的分子机制来确定Exor蛋白水解的分子机制及其调节；鉴定环境刺激调节驱虫蛋白水解，并鉴定梅洛利特巨蛋白酶蛋白酶。我们的新发现可以立即应用于对具有密切同源性链球菌的56种动物和植物病原体的致病性理解。我们的新发现将有助于发展新方法来控制细菌感染。 公共卫生相关性：在感知宿主的存在之后，大多数致病细菌产生了特殊的产品，以增强其感染宿主细胞的能力。我们的研究将通过阻止其感知宿主的能力来发展新方法来控制细菌感染。