CHLAMYDIAL INVASION OF NON-PHAGOCYTIC CELLS

衣原体侵入非吞噬细胞

• 批准号: 6952914
• 负责人: REY A CARABEO
• 金额: $ 32.16万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 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 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6952914
• 关键词: Chlamydia trachomatis; HeLa cells; actin binding protein; actins; bacteria infection mechanism; bacterial proteins; chlamydial disease; gene deletion mutation; guanine nucleotide binding protein; host organism interaction; immunoprecipitation; phagocytosis; phosphorylation; protein binding; protein protein interaction; protein structure function; proteomics

DESCRIPTION (provided by applicant): Chlamydia trachomatis is a Gram-negative obligate intracellular pathogen that is the causative agent of a wide spectrum of human diseases including trachoma and the sexually transmitted disease chlamydia. Successful infection of cells by chlamydia involves attachment, invasion, establishment of a protective vacuole called an inclusion, and inhibition of lysosomal fusion. With the advent of the C. trachomatis genome sequence and new cell biological and proteomic tools, the mechanisms involved in these processes are just beginning to be revealed, advancing our knowledge of chlamydia-host cell interactions. The long term goal is to define the molecular and biochemical mechanisms important for the successful establishment of infection by chlamydia. This proposal will specifically address the process of invasion. It is hypothesized that chlamydia uses multiple pathways of invading non-phagocytic cells. A recently identified molecule termed Tarp has been demonstrated to be translocated from the infecting elementary body across the host plasma membrane and into the cytosol where it is tyrosine phosphorylated by unknown host kinases, and recruit actin. As a phosphoprotein, Tarp may act as a signaling platform to recruit a number of adapter and effector molecules that mediate actin cytoskeletal remodeling. Specific Aim 1 will address the Rac GTPase dependent pathway and focus on the potential downstream mediators of actin recruitment. Specific Aim 2 will focus on the Tarp protein, the tyrosine kinase(s) responsible for its phosphorylation, the binding partners, their roles in chlamydial invasion, and the potential relationship of Tarp with the Rac GTPase. Specific Aim 3 will address the potential mechanism of actin recruitment by the Chlamydophila caviae Tarp homolog, which does not contain the multiple repeat sequences present in C. trachomatis serovars L2 and D. These studies would not only reveal important insights into the biology of chlamydia, but also the cellular process of signaling to the actin cytoskeleton that chlamydia subverts to facilitate its infection.

描述（由申请人提供）：沙眼衣原体是一种革兰氏阴性的细胞内病原体，是多种人类疾病（包括沙眼瘤和性传播性疾病衣原体）的病因。通过衣原体成功感染细胞涉及依恋，侵袭，建立称为包容性的保护性液泡以及抑制溶酶体融合。随着沙aratomis基因组序列以及新的细胞生物学和蛋白质组学工具的出现，这些过程中涉及的机制才刚刚开始揭示，从而促进了我们对衣原体 - 宿主宿主细胞相互作用的了解。长期目标是定义分子和生化机制对于成功建立衣原体感染很重要。该提案将特别解决入侵过程。假设衣原体使用多种入侵非吞噬细胞的途径。已证明最近鉴定出的称为TARP的分子已从宿主质膜上的感染基体转移到胞质溶液中，在那里它被未知的宿主激酶磷酸化，并募集肌动蛋白。作为一种磷蛋白，TARP可以充当信号平台，以募集许多介导肌动蛋白细胞骨架重塑的衔接子和效应分子。具体目标1将解决RAC GTPase依赖途径，并专注于肌动蛋白募集的潜在下游介体。具体的目标2将重点放在防水蛋白，酪氨酸激酶的磷酸化，结合伴侣，其在衣原体侵袭中的作用以及TARP与RAC GTPase的潜在关系。 Specific Aim 3 will address the potential mechanism of actin recruitment by the Chlamydophila caviae Tarp homolog, which does not contain the multiple repeat sequences present in C. trachomatis serovars L2 and D. These studies would not only reveal important insights into the biology of chlamydia, but also the cellular process of signaling to the actin cytoskeleton that chlamydia subverts to facilitate its infection.