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：
10656443
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/10656443
关键词：
Affect Alleles Animal Model Animals Antibiotics Bacteria Bacterial Infections Binding Biological Biology Cell physiology Cells Cellular biology Chlamydia Chlamydia Infections Chlamydia trachomatis Complex Defect Development Drug Targeting Ectopic Pregnancy Epithelium Genetic Goals Health Human Immunity Infection Infertility Inflammatory Response Integration Host Factors Invaded 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 conditional mutant design genetic approach genital infection in vivo infection rate loss of function mouse model mutant pathogen recruit reproductive organ reproductive tract therapeutic target therapeutically effective tissue culture transcriptomics transmission blocking

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起源性传播感染的主要原因。没有疫苗可用的。感染通常是无症状的，导致生殖器官的长期损害从骨盆炎症疾病到不育的人类健康的有害影响。发病机理是连接的宿主的炎症反应是由生殖道上皮的入侵而触发的细胞内病原体。衣原体细胞内生活方式的标志性和关键方面是其双重性发育周期，在此期间，细菌在传染（EB）和复制（RB）形式之间交替在膜结合室的腔内，称为包容性。控制机制通过发育周期的进展知之甚少。在这里，我们描述一个条件的衣原体纳入膜蛋白中的突变体。突变体显示出严重但互补的发展在发育周期的早期阶段的缺陷，最有可能在EB转换为RB转换。此外，这个Inc 当细菌退出时，蛋白质与参与发育周期晚期的宿主因子相互作用细胞通过挤出。我们建议测试该INC蛋白早期起双重作用的假设（AIM 1）和在发育周期期间迟到（AIM2），并确定其对发病机理的贡献（AIM 3）。通过细胞生物学，细菌遗传学，转录组学，蛋白质组学和体内方法的使用，我们的研究将进一步，我们对控制宿主 - 智慧相互作用的分子机制的理解发育周期。我们的工作总共有可能确定阻止治疗靶标与这种重要的性传播病原体有关的传播和发病机理。