Host-pathogen interactions controlling Chlamydia developmental cycle

宿主-病原体相互作用控制衣原体发育周期

基本信息

批准号：
10456920
负责人：
ISABELLE DERRE
金额：
$ 47.97万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10456920
关键词：
Affect Alleles Animal Model Animals Antibiotics Bacteria Bacterial Infections Biological Biology Cell physiology Cells Cellular biology Chlamydia Chlamydia Infections Chlamydia trachomatis Complement Complex Defect Development Drug Targeting Ectopic Pregnancy Epithelial Genetic Goals Health Human Immunity Infection Infertility Inflammatory Response Integration Host Factors Lead Left Life Style Link Membrane Membrane Proteins Molecular Morphology Nature Pathogenesis Pathology Pelvic Inflammatory Disease Phase Play Process Proteins Proteomics Reporting Reproductive Health Role STIM1 gene Sexual Transmission Sexually Transmitted Diseases Signal Transduction Stains Testing Tissues Vaccines Woman Work bacterial genetics base conditional mutant design genetic approach genital infection in vivo loss of function mouse model mutant pathogen recruit reproductive organ reproductive tract therapeutic target therapeutically effective tissue culture transcriptomics transmission process

项目摘要

SUMMARY Chlamydia trachomatis is the leading cause of sexually transmitted infections of bacterial origin. No vaccine is available. Infections are often asymptomatic, leading to long-term damage of the reproductive organs and deleterious effects on human health ranging from pelvic inflammatory disease to infertility. Pathogenesis is linked to a host inflammatory response triggered by the invasion of the genital tract epithelium with this obligate intracellular pathogen. A hallmark and critical aspect of Chlamydia intracellular life style is its bi-phasic developmental cycle, during which the bacteria alternate between infectious (EB) and replicative (RB) forms within the lumen of a membrane-bound compartment called the inclusion. The mechanisms that govern progression through the developmental cycle are poorly understood. Here we describe a Chlamydia conditional mutant in an inclusion membrane protein. The mutant displays a severe, yet complementable, developmental defect in the early stages of the developmental cycle, most likely during EB to RB conversion. Moreover, this Inc protein interacts with a host factor involved in the late stages of the developmental cycle, when the bacteria exit the cell via extrusion. We propose to test the hypothesis that this Inc protein plays a dual role early (Aim 1) and late (Aim2) during the developmental cycle and to determine its contribution to pathogenesis (Aim 3). Through the use of cell biology, bacterial genetics, transcriptomics, proteomics and in vivo approaches, our studies will further our understanding of the molecular mechanisms governing the host-Chlamydia interactions that control the developmental cycle. Altogether our work has the potential to identify therapeutic targets to block transmission of and pathogenesis associated with this important sexually transmitted pathogen.

概括沙眼衣原体是细菌性性传播感染的主要原因。没有疫苗可用的。感染通常无症状，导致生殖器官的长期损害和对人类健康产生有害影响，包括盆腔炎和不孕症。发病机制是相关的对由这种专性侵入生殖道上皮所引发的宿主炎症反应细胞内病原体。衣原体细胞内生活方式的一个标志和关键方面是其双相发育周期，在此期间细菌在感染性 (EB) 和复制性 (RB) 形式之间交替在称为包涵体的膜结合室的管腔内。治理机制人们对发育周期的进展知之甚少。在这里，我们描述了一种衣原体条件包涵膜蛋白的突变体。该突变体表现出严重但可互补的发育发育周期早期阶段的缺陷，最有可能是在 EB 到 RB 转换期间。而且，这家公司当细菌退出时，蛋白质与参与发育周期后期的宿主因子相互作用细胞通过挤压。我们建议检验这一假设，即该 Inc 蛋白在早期（目标 1）和发育周期的晚期（目标 2）并确定其对发病机制的贡献（目标 3）。通过利用细胞生物学、细菌遗传学、转录组学、蛋白质组学和体内方法，我们的研究将进一步我们对控制宿主-衣原体相互作用的分子机制的理解发育周期。总的来说，我们的工作有可能确定治疗靶点来阻止这种重要的性传播病原体的传播和发病机制。