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Molecular Determinants of Chlamydia Extrusion from Host Cells

衣原体从宿主细胞中挤出的分子决定因素

基本信息

批准号：
8836943
负责人：
Kevin Hybiske
金额：
$ 43.5万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-15 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8836943
关键词：
Actins Address Area Attention Bacteria Biology Calpain Caspase Cell membrane Cells Chlamydia Chlamydia Infections Chronic Communicable Diseases Complex Cytokinesis Cytolysis Data Development Disease Employee Strikes F-Actin Face Goals Growth Health Image Immune Immune response In Vitro Infection Infectious Agent Integration Host Factors Knowledge Life Malaria Mediating Membrane Microbiology Modeling Molecular Molecular Target Mus Myosin Type II Nuclear Envelope Parasites Pathogenesis Pathway interactions Play Process Proteins Recruitment Activity Research Research Proposals Residual state Rho-associated kinase Role Rupture Signal Pathway Signal Transduction Surface System Techniques Testing Therapeutic Intervention Time Translating Vacuole Visual Work antimicrobial base design genital infection in vitro Model in vivo innovation microbial novel novel therapeutics originality pathogen polymerization rho GTP-Binding Proteins signal processing therapeutic target tool transmission process

项目摘要

DESCRIPTION (provided by applicant): All intracellular pathogens must exit their host cells in order to disseminate and transmit to new hosts, yet this central theme has received little attention. The molecular mechanisms that control the exit of the intracellular bacterium Chlamydia from host cells are also poorly understood, and exemplify the greater gap in our understanding of this fundamental question in microbial pathogenesis. Using a novel imaging-based in vitro model, we have identified the two pathways by which Chlamydia exit cells at the end of their intracellular developmental cycle. One pathway, extrusion, is particularly innovative because of its originality and unique impact on dissemination and immune evasion. Our long-range goal is to understand the underlying molecular basis of and overall strategies used by intracellular pathogens to exit host cells. Our immediate objectives are to elucidate the molecular mechanisms of chlamydial extrusion and, for the first time, determine its role in pathogenesis in vivo. Here, we present data for the host cellular pathways engaged by Chlamydia during infection and that are required for extrusion from cells. We propose that Chlamydia specifically target these pathways via localized host-Chlamydia protein interactions on the vacuole membrane surface. The results of this work will profoundly enhance our understanding of microbial exit - a long unaddressed question in the field. Extrusion represents a new theme in host-pathogen interactions, and thus significant advances in our knowledge of this process at the mechanistic level and in the infected host should directly translate to other pathogen systems in which similar exit strategies are used, such as malarial parasites. Three key themes in chlamydial extrusion will be addressed by the following Specific Aims: (i) Identify the molecular mechanism for actin recruitment to the inclusion membrane; (ii) Define the host cytokinetic signaling networks responsible for the contraction step of extrusion; and (iii) Determine the functional role of extrusion in Chlamydia cell-to-cell spread and in vivo pathogenesis. Extrusion is a new paradigm in microbial pathogenesis. This novel exit mechanism likely plays a critical role in pathogen dissemination, transmission and immune evasion. We expect these studies to define the essential host factors involved for Chlamydia, and to illuminate the role extrusion plays in vivo. This research will have a significant impact on our understanding of an untapped area of microbiology. Finally, as new molecular targets are revealed by this work, we will also generate the tools and basis for a new therapeutic platform - leveraging microbial exit as a means of controlling infectious diseases.

描述（由申请人提供）：所有细胞内病原体必须离开其宿主细胞才能传播和传播到新的宿主，但这一中心主题很少受到关注。控制胞内细菌衣原体从宿主细胞中退出的分子机制也知之甚少，这使得我们对微生物发病机制中这一基本问题的理解存在更大的差距。使用一种新的成像为基础的体外模型，我们已经确定了两个途径，衣原体退出细胞在其细胞内发育周期结束。一种途径，挤出，是特别创新的，因为它的独创性和独特的影响传播和免疫逃避。我们的长期目标是了解潜在的分子基础和细胞内病原体退出宿主细胞的总体策略。我们的近期目标是阐明衣原体挤出的分子机制，并首次确定其在体内发病机制中的作用。在这里，我们目前的数据，宿主细胞的途径从事衣原体感染过程中，需要从细胞挤出。我们建议，衣原体特异性靶向这些途径，通过本地化的主机衣原体蛋白质相互作用的液泡膜表面。这项工作的结果将深刻地提高我们对微生物退出的理解-这是该领域长期未解决的问题。挤出代表了宿主-病原体相互作用的一个新主题，因此，我们在机械水平和受感染宿主中对这一过程的认识的重大进展应直接转化为使用类似退出策略的其他病原体系统，如疟疾寄生虫。衣原体挤出的三个关键主题将通过以下具体目标来解决：（i）确定肌动蛋白募集到包涵体膜的分子机制;（ii）定义负责挤出收缩步骤的宿主细胞动力学信号网络;（iii）确定挤出在衣原体细胞间传播和体内发病机制中的功能作用。挤压是微生物致病的一种新范式。这种新的退出机制可能在病原体传播、传播和免疫逃避中起关键作用。我们希望这些研究能够确定衣原体所涉及的基本宿主因素，并阐明挤出在体内所起的作用。这项研究将对我们理解微生物学的一个未开发领域产生重大影响。最后，由于这项工作揭示了新的分子靶点，我们还将为新的治疗平台提供工具和基础-利用微生物出口作为控制传染病的手段。