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

• 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
• 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

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.

衣原体III型效应因子影响宿主肌动蛋白基细胞骨架 摘要： 沙眼衣原体是一个重要的问题，人类健康的世界范围内，由于其流行和 急性和慢性疾病对健康和社会经济的综合影响。衣原体是专性的 细胞内病原体具有调节宿主细胞生物学的能力，同时被隔离在细胞内 被膜包围的寄生液泡。越来越多的证据表明III型分泌物 系统（T3 SS）代表了衣原体操纵这些细胞的重要机制。 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制代表了 衣原体介导的改变的主要目标。我们发现了一种新的途径 细胞内披衣细胞重定向宿主细胞囊泡运输。这种机制需要分支的 肌动蛋白网络和至少两种命名为TmeA和TmeB的III型分泌效应物。我们建议 解决这一假设，这些效应差异调节分支肌动蛋白网络， 通过施加宿主Arp 2/3的轴来完成宿主细胞资源向成熟包涵体的运输 activation.我们建议阐明的分子细节，其中的联合活动的C。沙眼衣原体 TmeA和TmeB影响宿主细胞，促进细胞内发育和逃避细胞内宿主 的防御合作.相应的C.将使用鼠伤寒沙门氏菌突变株来阐明 在动物模型中这些效应物对发病机制的影响。基因，生化， 细胞生物学和动物为基础的研究提出，将确定这些效应器的整体作用， 建立和维持传染性，最终导致衣原体介导的疾病。完成 这项工作将有助于加深对衣原体分子机制的理解 影响宿主-病原体相互作用控制疾病。