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: 10528480
• 负责人: ISABELLE DERRE
• 金额: $ 23.26万
• 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 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10528480
• 关键词: Antibiotics; Bacteria; Bacterial Infections; Binding; Biological; Biotin; C-terminal; Cells; Cellular biology; Chlamydia; Chlamydia Infections; Chlamydia trachomatis; Cholesterol; Cicatrix; Communication; Complex; Cytolysis; Data; Development; Ectopic Pregnancy; Endoplasmic Reticulum; Ensure; Environment; Epithelium; Female; Functional disorder; Growth; Immunity; Infection; Infertility; Integration Host Factors; Label; 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; candidate identification; design; follow-up; genital infection; human disease; infection rate; 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.

总结 沙眼衣原体是全世界细菌性传播感染的主要原因。 没有疫苗。感染通常是无症状的，未经治疗，导致组织瘢痕形成， 对女性生殖健康的长期影响。C.沙眼是一种专性细胞内细菌途径， 在膜结合隔室内经历双相发育周期的原，称为inclu， 锡永。为了在这种封闭的环境中茁壮成长，C。沙眼必须与胞质宿主因子和有机体相互作用， nelles，一个由衣原体特异性包涵体膜蛋白（Inc蛋白）插入介导的过程 进入包合膜。一种这样的相互作用是包含体的离散部分之间的紧密接触， 锡永网（ER）是内质网的重要组成部分。这些结构被称为ER-包含膜 联系网站（MCS）。我们对ER-包涵体MCS的初步表征表明富含Inc蛋白， 具有功能、约束和监管能力的宿主因素。其中一些成分的消耗是 对细菌生长有害，强调了ER-包涵体MCS在建立 复制生态位。在整个发育周期中都观察到ER内含物MCS;然而，它仍然存在 不清楚功能性、结构性和规则性成分是否以及如何在颞叶组装中合作， 接触的溶解性和特定成分的富集。在这里，我们将探讨如何ER包容 MCS组装受到管制（目标1），如果特定组件的关联因组装阶段而异， 发展周期（目标2）。总之，拟议的研究将阐明ER-包涵体的组成部分 MCS允许建立C.沙眼复制生态位，这将指导设计有效的 治疗学