Regulation and composition of ER-inclusion contacts at key stages of the Chlamydia developmental cycle

衣原体发育周期关键阶段 ER 包涵体接触的调控和组成

• 批准号: 10352503
• 负责人: ISABELLE DERRE
• 金额: $ 19.22万
• 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: 2021-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10352503
• 关键词: Antibiotics; Bacteria; Bacterial Infections; Biological; Biotin; C-terminal; Cell membrane; Cells; Cellular biology; Chlamydia; Chlamydia Infections; Chlamydia trachomatis; Cholesterol; Cicatrix; Communication; Complex; Cytolysis; Data; Development; Ectopic Pregnancy; Endoplasmic Reticulum; Ensure; Environment; Epithelial; Female; Functional disorder; Growth; Immunity; Infection; Infertility; Integration Host Factors; Label; Lead; Left; Lipids; Mediating; Membrane; Membrane Biology; Membrane Proteins; Microbiology; Molecular; Organelles; Pelvic Inflammatory Disease; Phase; Phosphorylation; Phosphotransferases; Process; Proteins; Proteome; Regulation; Reproductive Health; Role; Serine; Sexually Transmitted Diseases; Site; Structure; Testing; Time; Tissues; Vaccines; Woman; Work; design; follow-up; genital infection; human disease; novel; pathogen; pathogenic bacteria; prevent; recruit; reproductive organ; therapeutically effective; trafficking

SUMMARY Chlamydia trachomatis is the leading cause of sexually transmitted infections of bacterial origin worldwide. Vaccines are not available. Infections are often asymptomatic and left untreated, resulting in tissue scarring and long-term consequences on female reproductive health. C. trachomatis is an obligate intracellular bacterial path- ogen that undergoes a bi-phasic development cycle within a membrane bound compartment termed the inclu- sion. To thrive in this confined environment, C. trachomatis must interact with cytosolic host factors and orga- nelles, a process mediated by the insertion of Chlamydia specific Inclusion membrane proteins (Inc proteins) into the inclusion membrane. One such interaction is the intimate contact between discrete sections of the inclu- sion membrane and the endoplasmic reticulum (ER). These structures are referred to as ER-Inclusion membrane contact sites (MCS). Our initial characterization of ER-Inclusion MCS indicates an enrichment in Inc proteins and host factors with functional, tethering and regulatory capacities. Depletion of some of these components is detrimental to bacterial growth, underscoring the important role of ER-Inclusion MCS in establishing the replicative niche. ER-Inclusion MCS are observed throughout the developmental cycle; however, it remains unclear if and how functional, structural and regularoty components cooperate in the temporal assembly and dissambly of the contact, and enrichment of specific components. Here we will investigate how ER-Inclusion MCS assembly is regulated (Aim 1) and if association of specific components varies depending on the stage of the developmental cycle (Aim 2). Altogether, the proposed studies will elucidate how components of ER-Inclusion MCS allows for the establishment of the C. trachomatis replicative niche, which will guide the design of effective therapeutics.

概括 沙眼衣原体是全世界细菌性性传播感染的主要原因。 没有疫苗。感染通常无症状且未经治疗，导致组织疤痕和 对女性生殖健康的长期影响。沙眼衣原体是一种专性细胞内细菌路径 基因在膜结合区室中经历双相发育周期，称为包含 锡安。为了在这种有限的环境中茁壮成长，沙眼衣原体必须与胞质宿主因子和有机体相互作用。 nelles，由衣原体特异性包涵体膜蛋白（Inc 蛋白）插入介导的过程 进入包涵膜。其中一种相互作用是包括在内的离散部分之间的密切接触。 离子膜和内质网（ER）。这些结构被称为 ER 包涵体膜 联系站点 (MCS)。我们对 ER-Inclusion MCS 的初步表征表明 Inc 蛋白和 具有功能、束缚和调节能力的宿主因子。其中一些成分的消耗是 不利于细菌生长，强调了 ER-Inclusion MCS 在建立细菌生长中的重要作用 复制生态位。在整个发育周期中观察到 ER-Inclusion MCS；然而，它仍然 不清楚功能、结构和规律成分是否以及如何在时间组装和 接触的分解和特定组件的浓缩。在这里我们将研究 ER-Inclusion 如何 MCS 组装受到监管（目标 1），并且特定组件的关联是否根据组装阶段而变化 发展周期（目标 2）。总而言之，拟议的研究将阐明 ER-Inclusion 的组成部分如何 MCS 允许建立沙眼衣原体复制生态位，这将指导有效的设计 疗法。