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

• 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
• 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

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.

摘要 沙眼衣原体是细菌性传播感染的主要原因。没有疫苗是 可用。感染通常是无症状的，导致生殖器官和 对人类健康的有害影响从盆腔炎到不孕不育。病机相通 对由生殖道上皮侵入引起的宿主炎症反应具有这种专性 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它的双相 细菌在感染型(EB)和复制型(RB)之间交替的发育周期 在一个称为包裹物的膜结合室的管腔内。治理的机制 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 包涵膜蛋白中的突变体。突变体表现出严重的，但可互补的发育 发育周期早期的缺陷，很可能在EB向RB转化期间。此外，这一公司 当细菌退出时，蛋白质与参与发育周期后期阶段的宿主因子相互作用 通过挤压将单元格。我们建议在早期(目标1)测试该Inc蛋白起双重作用的假设 在发育周期中晚期(AIM2)，并确定其在发病机制中的作用(目标3)。穿过 利用细胞生物学、细菌遗传学、转录组学、蛋白质组学和活体方法，我们的研究将 进一步了解控制宿主-衣原体相互作用的分子机制 发育周期。总之，我们的工作有可能确定要阻断的治疗靶点 这种重要的性传播病原体的传播和发病机制。