Regulation of Pore Formation by Type III Secretion System

III 型分泌系统对毛孔形成的调节

• 批准号: 7924020
• 负责人: Gloria I Viboud
• 金额: $ 19.63万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7924020
• 关键词: Actins; Adhesions; Antigens; Bacteria; Binding; Bioterrorism; Cell membrane; Cell physiology; Cells; Code; Complex; Confocal Microscopy; Cytoplasm; Cytoskeleton; Dominant-Negative Mutation; Epithelial Cells; Event; Family; Genes; Glycosphingolipids; Hela Cells; Homologous Protein; Human; Image; Immune system; Immunoprecipitation; Infection; Integrins; Intestines; Knock-out; Life; Light; Lymphoid Tissue; Mediating; Membrane; Membrane Proteins; Modeling; Modification; Molecular; Monoclonal Antibodies; Nature; Needles; Organism; Pasteurella pseudotuberculosis; Pathogenesis; Pathway interactions; Plague; Plasmids; Play; Pneumonia; Pneumonic Plague; Process; Proteins; Pseudomonas; Pseudomonas aeruginosa; Receptor Cell; Regulation; Research; Research Project Grants; Role; Salmonella; Shigella; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Structure; Syringes; Testing; Toxin; Travel; Type III Secretion System Pathway; Virulence; Yersinia; Yersinia enterocolitica; Yersinia pestis; antimicrobial; appendage; base; clinically significant; enteropathogenic Escherichia coli; inhibitor/antagonist; mutant; novel; pathogen; polymerization; rho; rho GTP-Binding Proteins

DESCRIPTION (provided by applicant): The type III secretion system (TTSS) is essential for the pathogenesis of a number of gram-negative human pathogens, including three Yersinia species; Y. pseudotuberculosis and Y. enterocolitica, that cause infection of intestinal lymphoid tissues, and Y. pestis, the etiological agent of bubonic and pneumonic plague. In Yersinia, the TTSS is composed of a needle-like structure, three translocator proteins involved in the delivery of toxins into the host cell (YopB, YopD and LcrV), and six effector proteins (YopE, YopT, YopH, YopJ, YopO, YopM) that target different host cell signaling molecules to disarm the innate and adaptive host immune system. YopB and YopD are thought to insert in the plasma membrane forming a translocation channel. Wild type Yersinia does not disrupt the integrity of the host cell membrane during the translocation process. Bacteria deficient in YopE and YopT, or expressing a form of the two proteins unable to down-regulate Rho GTPases, have strong pore forming activity. We have found that pore formation results from a Yersinia-induced host cell signaling that requires YopB and YopD, and that is blocked by inactivation of Rho GTPases. Here, we postulate that activation of such signaling pathways might also be required for an efficient translocation process. We will aim to determine a) what signaling events are required for pore formation, and whether those signals play a role in translocation; b) whether activation of additional host cell signals, such as the 21 integrin pathway, may be involved in pore formation or translocation; c) whether YopD may stimulate host-signaling functions by interacting with host cell partners. The type III secretion system (TTSS) is essential for the virulence of a number of gram- negative human pathogens of enormous clinical significance. Some of these organisms include important entropathogens such as Salmonella spp., Shigella spp., Yersinia enterocolitica, Y. pseudotuberculosis and enteropathogenic Escherichia coli as well agents causing severe pneumonia, like the opportunistic bacteria Pseudomonas aeruginosa, or the deadly Yersinia pestis. Interestingly, Y. pestis, the etiological agent of plague, and a currently considered a class A bioterrorism agent, is closely related to Y. pseudotubeculosis, which causes an infection limited to intestinal lymphoid tissues. The studies proposed in this application constitute the frame of an exploratory research project aim at testing a new hypothesis: that the TTSS of Yersinia manipulates the host cell machinery to inject its own toxins. This type III-mediated signaling may not be restricted to Yersinia and might take place during infection of host cells with other pathogens that encode homologs of proteins, such as enteropathogenic E. coli, Shigella, and Salmonella. Studies that answer these questions might shed light on the molecular nature of the complex interaction between bacterial pathogens bearing TTSSs and the host cell. Importantly, components that act by modulating the TTSS are potential targets for novel antimicrobials.

描述（由申请人提供）：III型分泌系统（TTSS）对于许多革兰氏阴性人类病原体（包括三种耶尔森氏菌种类）的发病机理至关重要。 Y.假结核和小肠结肠炎，引起肠道淋巴组织的感染，以及鼠疫霉菌（Bubonic和肺炎鼠疫的病因学剂）。 In Yersinia, the TTSS is composed of a needle-like structure, three translocator proteins involved in the delivery of toxins into the host cell (YopB, YopD and LcrV), and six effector proteins (YopE, YopT, YopH, YopJ, YopO, YopM) that target different host cell signaling molecules to disarm the innate and adaptive host immune system. YOPB和YOPD被认为插入形成易位通道的质膜中。在易位过程中，野生型Yersinia不会破坏宿主细胞膜的完整性。缺乏YOPE和YOPT的细菌，或表达无法下调Rho GTPase的两种蛋白质的形式，具有强大的孔形成活性。我们发现，孔形成是由耶尔森尼亚诱导的宿主细胞信号传导引起的，需要YOPB和YOPD，并且由于Rho GTPases的失活而阻止了孔。在这里，我们假设有效的易位过程也可能需要这种信号通路的激活。我们将旨在确定孔形成需要哪些信号事件，以及这些信号是否在易位中起作用； b）其他宿主信号的激活（例如21整合素途径）是否可能参与孔形成或易位； c）YOPD是否可以通过与宿主细胞伴侣相互作用来刺激宿主信号功能。 III型分泌系统（TTSS）对于许多具有巨大临床意义的革兰氏阴性人类病原体的毒力至关重要。其中一些有机体包括重要的肠病毒，例如沙门氏菌，志贺氏菌，小肠结尾耶尔西尼亚，Y.伪结核和肠病毒性大肠杆菌以及造成严重肺炎的特工，例如机会性细菌，例如机会性细菌，pseudomonas erugoginosa，或deadeai yersiaiaiaia pestis pestis。有趣的是，鼠疫的病因学药Y.本应用程序中提出的研究构成了探索性研究项目的框架，旨在检验一个新的假设：耶尔森氏菌的TTSS操纵宿主细胞机械以注入自己的毒素。这种类型的III介导的信号可能不限于耶尔森氏菌，可能在宿主细胞感染期间与其他编码蛋白质同源物的病原体（例如肠病毒大肠杆菌，志贺氏菌和沙门氏菌）进行。回答这些问题的研究可能会阐明带有TTSS和宿主细胞的细菌病原体之间复杂相互作用的分子性质。重要的是，通过调节TTSS来起作用的组件是新型抗菌剂的潜在靶标。