Chlamydial invasion of non-phagocytic cells

衣原体侵入非吞噬细胞

• 批准号: 10078928
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10078928
• 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; Genitalia; 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.

项目总结 沙眼衣原体是中国最流行的性传播感染(STI)的病原体。 工业化国家和不发达国家的致盲疾病沙眼。有一个 据估计，全世界每年新报告的性病衣原体感染病例为9300万例。沙眼影响 大约1.5亿人，主要是妇女和儿童。两种疾病的病理特征 疾病是慢性炎症造成的疤痕；以及在疾病早期阶段的炎症 感染是由上皮细胞感染引发的，由活跃的细菌复制和持续 沿着生殖器和眼粘膜扩散。 衣原体是一种革兰氏阴性的细胞内专性病原体，这意味着它需要细胞内的 为其生存和繁殖创造的环境。因此，对允许的宿主细胞的入侵对其 生存和发病机制。在体内，主要的目标是排列在眼睛和生殖器上的上皮细胞 粘液。我们的主要假设是，入侵是一个由衣原体驱动的过程。这种病原体有 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 形成旨在吞噬细菌的细胞表面结构。入侵涉及多个信号 正常细胞中的通路在调节肌动蛋白细胞骨架动力学中发挥作用。这种细菌会打开 机械在其粘连部位，肌动蛋白重塑的位置由限制性决定 衣原体毒力蛋白TARP转位到宿主细胞质的胞浆侧 薄膜。TARP招募了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，如果持续下去，会导致组织损伤和结膜疤痕形成 导致不育的生殖道。因此，衣原体致病的能力始于入侵。 虽然我们对TARP在入侵过程中的功能有了更好的了解，但它是如何 监管是稀疏的。本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。将实现以下具体目标。I)确定 TARP在侵袭中的机制及其意义II)确定肌球蛋白II的调控 衣原体侵入体组分；以及iii)确定肌动蛋白后摄取的机制 招聘。目标是对TARP的功能和调节有一个详细的了解，以便指导 合理的药物和疫苗设计，以对抗衣原体感染。

项目成果

A Functional Slow Recycling Pathway of Transferrin is Required for Growth of Chlamydia.

• DOI: 10.3389/fmicb.2010.00112
• 发表时间: 2010
• 期刊: Frontiers in microbiology
• 影响因子: 5.2
• 作者: Ouellette SP;Carabeo RA
• 通讯作者: Carabeo RA

Chlamydial YAP activation in host endocervical epithelial cells mediates pro-fibrotic paracrine stimulation of fibroblasts.

• DOI: 10.1128/msystems.00904-23
• 发表时间: 2023-12-21
• 期刊: mSystems
• 影响因子: 6.4

Manipulation of the Host Cell Cytoskeleton by Chlamydia.

衣原体对宿主细胞细胞骨架的操纵。

• DOI: 10.1007/82_2016_10
• 发表时间: 2018
• 期刊: Current topics in microbiology and immunology
• 作者: Nogueira,AnaT;Pedrosa,AntonioT;Carabeo,ReyA
• 通讯作者: Carabeo,ReyA

Dynamin-dependent entry of Chlamydia trachomatis is sequentially regulated by the effectors TarP and TmeA.

沙眼衣原体的动力依赖性进入依次受到效应子 TarP 和 TmeA 的调节。

• DOI: 10.21203/rs.3.rs-3376558/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Romero,MatthewD;Carabeo,ReyA
• 通讯作者: Carabeo,ReyA

A post-invasion role for Chlamydia type III effector TarP in modulating the dynamics and organization of host cell focal adhesions.

• DOI: 10.1074/jbc.ra120.015219
• 发表时间: 2020-10-23
• 期刊: The Journal of biological chemistry
• 作者: Pedrosa AT;Murphy KN;Nogueira AT;Brinkworth AJ;Thwaites TR;Aaron J;Chew TL;Carabeo RA
• 通讯作者: Carabeo RA