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

• 批准号: 8653528
• 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
• 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/8653528
• 关键词: Actins; Address; Area; Attention; Bacteria; Biology; Calpain; Cell membrane; Cells; Chlamydia; Chlamydia Infections; Chronic; Communicable Diseases; Complex; Cysteine Protease; Cytokinesis; Cytolysis; Data; Development; Disease; Employee Strikes; F-Actin; Face; Goals; Growth; 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; public health relevance; rho GTP-Binding Proteins; signal processing; therapeutic target; tool; transmission process

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并传播给新宿主，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排出的分子机制也知之甚少，这说明我们对微生物发病机制这一基本问题的理解存在更大差距。使用基于成像的新型体外模型，我们确定了衣原体在细胞内发育周期结束时退出细胞的两条途径。其中一种途径“挤出”尤其具有创新性，因为它具有独创性以及对传播和免疫逃避的独特影响。我们的长期目标是了解细胞内病原体离开宿主细胞的潜在分子基础和总体策略。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，我们提供了衣原体在感染过程中参与的宿主细胞途径的数据，以及从细胞中挤出所需的数据。我们认为衣原体通过液泡膜表面上的局部宿主-衣原体蛋白相互作用来特异性靶向这些途径。这项工作的结果将深刻地增强我们对微生物退出的理解——这是该领域长期未解决的问题。挤出代表了宿主与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了解的重大进展应该直接转化为使用类似退出策略的其他病原体系统，例如疟疾寄生虫。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膜的分子机制； (ii) 定义负责挤出收缩步骤的宿主细胞因子信号网络； (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。 挤压是微生物发病机制的一个新范例。这种新颖的退出机制可能在病原体传播、传播和免疫逃避中发挥关键作用。我们期望这些研究能够定义衣原体所涉及的重要宿主因素，并阐明挤出在体内的作用。这项研究将对我们对微生物学尚未开发的领域的理解产生重大影响。最后，随着这项工作揭示了新的分子靶点，我们还将为新的治疗平台生成工具和基础——利用微生物退出作为控制传染病的手段。