Chlamydia type III effectors affecting the host actin-based cytoskeleton

III 型衣原体效应子影响宿主肌动蛋白细胞骨架

基本信息

批准号：
10632935
负责人：
KENNETH A FIELDS
金额：
$ 57.4万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-06 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10632935
关键词：
Actins Acute Disease Address Affect Animal Model Animals Binding Biochemical Biological Biology Cell membrane Cell physiology Cells Cellular biology Chlamydia Chlamydia Infections Chlamydia muridarum Chlamydia trachomatis Chronic Disease Communities Cytoskeleton Data Detection Development Disease Disease Progression Epithelial Cells Event Genetic Grant Growth Health Host Defense Human Immune In Vitro Infection Invaded Link Lipids Mediating Membrane Microbiology Modeling Modification Molecular Mus Mutation Organelles Outcome Pathogenesis Pathology Pathway interactions Polymers Prevalence Process Proteins Resources Role Science Sexually Transmitted Agents Sexually Transmitted Diseases Source Testing Time Type III Secretion System Pathway Vacuole Virulence Work comparative design economic impact health economics human pathogen immunopathology in vivo member mutant novel obligate intracellular parasite parasitism pathogen polymerization reproductive tract socioeconomics trafficking vesicle transport

项目摘要

Grant title: Chlamydia type III effectors affecting the host actin-based cytoskeleton Abstract: Chlamydia trachomatis is a significant concern for human health world-wide due to its prevalence and the combined health and socioeconomic impact of acute and chronic disease. Chlamydiae are obligate intracellular pathogens that possess the ability to modulate host-cell biology while sequestered within a membrane-bound parasitophorous vacuole. Accumulating evidence indicates that a type III secretion system (T3SS) represents a significant mechanism employed by chlamydiae to manipulate these critical host cell functions. The host actin cytoskeleton and vesicular transport machinery represent major targets for Chlamydia-mediated alterations. We have identified a novel pathway by which intracellular chlamydiae redirect host cell vesicular trafficking. This mechanism requires the branched actin network and at least two type III secretion effectors designated TmeA and TmeB. We propose to address the hypothesis that these effectors differentially modulate branched actin networks to accomplish trafficking of host-cell resources to the mature inclusion by imposing an axis of host Arp2/3 activation. We propose to elucidate molecular details by which the combined activities of C. trachomatis TmeA and TmeB affect host cells to promote intracellular development and evasion of cell-intrinsic host defenses. Corresponding C. muridarum mutant strains will be employed to elucidate the contributions of these effectors to pathogenesis in an animal model. A balanced combination of genetic, biochemical, cell-biology, and animal-based studies are proposed that will define the overall role of these effectors in establishing and maintaining infectivity that culminates in Chlamydia-mediated disease. Completion of this work will lead to an enhanced understanding of the molecular mechanisms employed by Chlamydia to impact host-pathogen interactions governing disease.

赠款标题：影响宿主基于肌动蛋白的细胞骨架的第三型衣原体抽象的：沙眼衣原体由于其流行和急性和慢性疾病的健康和社会经济的综合影响。衣原体具有义务具有调节宿主细胞生物学能力的细胞内病原体，同时隔离膜结合的寄生虫液泡。积累的证据表明III型分泌系统（T3SS）代表衣原体采用的重要机制来操纵这些机制关键的宿主细胞功能。宿主肌动蛋白细胞骨架和囊泡运输机械代表衣原体介导的改变的主要靶标。我们已经确定了一种新颖的途径细胞内衣原体重定向宿主细胞囊泡运输。这种机制需要分支肌动蛋白网络和至少两个III型分泌效应子指定TMEA和TMEB。我们建议解决了这些效应子将分支肌动蛋白网络差异化的假设通过施加宿主ARP2/3的轴来完成将宿主资源贩运到成熟的包含激活。我们提议阐明分子细节，使沙眼的合并活性通过 TMEA和TMEB会影响宿主细胞，以促进细胞内发育和逃避细胞中性宿主防御。将采用相应的Muridarum C. muridarum突变菌株来阐明贡献这些对动物模型中发病机理的影响。遗传，生化，平衡的组合提出了细胞生物学和基于动物的研究，以定义这些效应子在建立和维持感染性，最终导致衣原体介导的疾病。完成这项工作将导致对衣原体采用的分子机制的增强理解影响控制疾病的宿主病原体相互作用。