Chlamydial invasion of non-phagocytic cells

衣原体侵入非吞噬细胞

• 批准号: 10032822
• 负责人: REY A CARABEO
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10032822
• 关键词: Actins; Address; Adherence; Affect; Antibiotics; Apical; Bacteria; Biochemical; Case Study; Caveolae; Cell Communication; Cell Line; Cell membrane; Cell physiology; Cell surface; Cells; Child; Chlamydia; Chlamydia Infections; Chlamydia trachomatis; Chronic; Cicatrix; Clathrin; Cytoskeleton; Data; Developed Countries; Developing Countries; Disease; Drug Design; Endocytosis; Environment; Epithelial Cells; Etiology; Event; Exhibits; Fluorescence Microscopy; Funding; Genital system; Goals; Image; Individual; Infection; Infertility; Inflammation; Link; Location; Lysosomes; Mediating; Microtubule-Associated Proteins; Molecular; Molecular Conformation; Monitor; Mucous Membrane; Myosin Type II; Normal Cell; Outcome; Pathogenesis; Pathologic; Pathway interactions; Plasma Cells; Play; Process; Property; Proteins; Proteomics; Receptor Cell; Regulation; Research; Role; Sexually Transmitted Diseases; Side; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Signaling Protein; Site; Stretching; Structural Protein; Structure; Tissues; Trachoma; Vaccine Design; Vacuole; Vinculin; Virulence; Virulence Factors; Woman; bulbar conjunctiva; combat; design; in vivo; insight; live cell imaging; mechanotransduction; non-muscle myosin; novel; pathogen; receptor; recruit; reproductive tract; trafficking; transmission process; uptake; vaccine development

PROJECT SUMMARY Chlamydia trachomatis is the etiologic agent of the most prevalent sexually transmitted infection (STI) in industrialized nations and the blinding condition, trachoma, in under-developed countries. There is an estimated 93 million new reported cases of Chlamydia STI annually worldwide. Trachoma affects approximately 150 million individuals, predominantly women and children. The pathologic hallmark of both diseases is the scarring the results from chronic inflammation; and inflammation at the very early stages of infection is initiated by infection of epithelial cells, and sustained by active bacterial replication and dissemination along the genital and ocular mucosae. Chlamydia is a Gram-negative obligate intracellular pathogen, which means that it requires an intracellular environment for its survival and replication. Hence, invasion of a permissive host cell is paramount to its survival and pathogenesis. In vivo, the primary target is the epithelial cells that line the ocular and genital mucosae. Our overarching hypothesis is that invasion is a Chlamydia-driven process. This pathogen has evolved mechanisms of manipulating the host cell actin cytoskeleton of to induce its uptake, leading to the formation of cell surface structures designed to engulf the bacteria. Invasion involves a number of signaling pathways that in normal cells play a role in regulating actin cytoskeleton dynamics. The bacteria turns on the machinery at its site of adherence, with the location of actin remodeling determined by the restricted translocation of a chlamydial virulence protein called TarP to the cytosolic side of the host cell plasma membrane. TarP recruits a number of signaling molecules to initiate the remodeling of the actin cytoskeleton, followed by the engulfment of the pathogen. Once inside the cell, the pathogen has the opportunity to hijack other cellular processes, including the initiation of inflammation, which when sustained leads to tissue damage and scarring of the ocular conjunctiva the genital tract resulting in infertility. Thus, the ability of Chlamydia to cause disease starts with invasion. While we have a better understanding of TarP function during invasion, mechanistic details on how it is regulated is sparse. This application will investigate the role of mechanotransduction in regulating TarP interactions with host signaling molecules. The following Specific Aims will be addressed. I) To identify the mechanism and significance of TarP mechanosensing in invasion; II) To define the myosin II-regulated components of the chlamydial invasome; and III) To determine the mechanism of uptake post-actin recruitment. The goal is to obtain a detailed understanding of TarP function and regulation in order to guide rational drug and vaccine designs to combat Chlamydia infections.

项目摘要 沙眼衣原体是最普遍的性传播感染（STI）的病因学药 工业化国家和盲目的沙洲，在欠发达国家。有一个 估计每年在全球范围内有9300万个新报告的衣原体STI病例。沙眼会影响 大约有1.5亿个人，主要是妇女和儿童。两者的病理标志 疾病是慢性炎症结果的疤痕。和炎症在很早的阶段 感染是通过感染上皮细胞引发的，并通过活性细菌复制和 沿着生殖器和眼粘的传播。 衣原体是一种革兰氏阴性的细胞内病原体，这意味着它需要细胞内 其生存和复制的环境。因此，允许宿主细胞的入侵对其至关重要 生存和发病机理。在体内，主要靶标是对眼和生殖器的上皮细胞 粘膜。我们的总体假设是入侵是一个由衣原体驱动的过程。该病原体具有 操纵宿主细胞肌动蛋白细胞骨架以诱导其摄取的进化机制，导致 旨在吞噬细菌的细胞表面结构的形成。入侵涉及多种信号 正常细胞中的途径在调节肌动蛋白细胞骨架动力学中起作用。细菌打开 在其依从性地点的机械，肌动蛋白重塑的位置由受限 称为TARP的衣原体毒力蛋白的易位到宿主细胞等离子体的胞质侧 膜。 TARP募集许多信号分子来启动肌动蛋白细胞骨架的重塑， 然后是病原体的吞没。 一旦进入细胞，病原体就有机会劫持其他细胞过程，包括 炎症的启动，炎症会持续会导致组织损伤和眼膜疤痕 生殖道导致不育症。因此，衣原体引起疾病的能力始于入侵。 虽然我们对入侵期间的篷布功能有更好的了解，但有关它的机理细节 调节很少。该应用将调查机械转移在调节篷布中的作用 与宿主信号分子的相互作用。将解决以下特定目标。 i）确定 篷布在侵袭中的机理和意义； ii）定义肌球蛋白II调节 衣原体入侵组的组成部分； iii）确定摄取后肌动蛋白的机制 招聘。目的是获得对TARP功能和调节的详细理解，以指导 合理的药物和疫苗设计以对抗衣原体感染。