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 沙眼衣原体是全球细菌起源性传播感染的主要原因。 疫苗不可用。感染通常是无症状的，没有治疗，导致组织疤痕和 长期对女性生殖健康的后果。沙丘梭状庭是一种强制性细胞内细菌途径 - 在膜结合室内经历双重发展周期的OGEN称为包含的 锡。为了在这种狭窄的环境中壮成长，沙眼梭菌必须与胞质宿主因子和orga-相互作用 NELLES，这是通过插入衣原体包含膜蛋白（INC蛋白）介导的过程 进入包含膜。这种相互作用之一是包含的离散部分之间的亲密接触 膜膜和内质网（ER）。这些结构被称为ER包含膜 接触站点（MC）。我们对ER的最初表征MC，表明INC蛋白质的富集和 具有功能，束缚和监管能力的宿主因素。其中一些组件的耗竭是 不利于细菌生长，强调了ER纳入MC在建立 复制的利基。在整个发育周期中都观察到ER融合MC；但是，它仍然是 不清楚在时间组装中的功能，结构和常规组件是否合作，以及 接触不舒服，并富集特定的组件。在这里，我们将调查如何包含ER MCS组装受到调节（AIM 1），如果特定组件的关联会根据 发展周期（AIM 2）。总共提出的研究将阐明ER融合的组成部分 MCS允许建立沙眼C. c. c. 疗法。