Chlamydial invasion of non-phagocytic cells

衣原体侵入非吞噬细胞

基本信息

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
项目类别：
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

项目摘要

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.

项目概要沙眼衣原体是最常见的性传播感染 (STI) 的病原体工业化国家和欠发达国家的致盲疾病沙眼。有一个据估计，全球每年新报告的衣原体性传播感染病例为 9300 万例。沙眼影响大约有 1.5 亿人，其中主要是妇女和儿童。两者的病理特征疾病是慢性炎症造成的疤痕；以及早期阶段的炎症感染由上皮细胞感染引发，并由活跃的细菌复制和维持沿生殖器和眼粘膜传播。衣原体是一种革兰氏阴性专性细胞内病原体，这意味着它需要细胞内其生存和复制的环境。因此，允许的宿主细胞的入侵对于其生存至关重要。生存和发病机制。在体内，主要目标是排列在眼睛和生殖器上的上皮细胞粘膜。我们的首要假设是入侵是衣原体驱动的过程。这种病原体有进化出操纵宿主细胞肌动蛋白细胞骨架以诱导其摄取的机制，从而导致形成旨在吞噬细菌的细胞表面结构。入侵涉及许多信号正常细胞中在调节肌动蛋白细胞骨架动力学中发挥作用的途径。细菌会开启机械在其粘附部位，肌动蛋白重塑的位置由限制性决定称为 TarP 的衣原体毒力蛋白易位至宿主细胞血浆的胞质侧膜。 TarP 招募许多信号分子来启动肌动蛋白细胞骨架的重塑，接下来是病原体的吞噬。一旦进入细胞，病原体就有机会劫持其他细胞过程，包括引发炎症，持续时会导致组织损伤和眼结膜疤痕生殖道导致不孕。因此，衣原体引起疾病的能力始于入侵。虽然我们对入侵过程中 TarP 的功能有了更好的了解，但它的机制细节监管稀疏。该应用将研究机械转导在调节 TarP 中的作用与宿主信号分子的相互作用。将解决以下具体目标。一）识别 TarP机械传感入侵的机制及意义； II) 定义肌球蛋白 II 调节的衣原体侵袭体的成分； III) 确定肌动蛋白后的摄取机制招聘。目标是详细了解 TarP 的功能和调节，以指导合理的药物和疫苗设计来对抗衣原体感染。