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Primary cilia loss and cell cycle re-entry in Chlamydia-infected cells

衣原体感染细胞中的初级纤毛丢失和细胞周期重新进入

基本信息

批准号：
10436218
负责人：
CHRISTINE SUETTERLIN
金额：
$ 55.17万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-17 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10436218
关键词：
Antibodies Bacteria Biology Cell Culture Techniques Cell Cycle Cell Cycle Progression Cell Differentiation process Cell Line Cell surface Cells Centers for Disease Control and Prevention (U.S.)Centrosome Chlamydia Chlamydia Infections Chlamydia trachomatis Cilia Communicable Diseases Country Data Development Disease Notification Environment Epithelial Cells Flow Cytometry G1/S Transition Goals Growth HDAC6 gene Infection Intervention Knowledge Lead Learning Link Malignant Neoplasms Measures Methods Microbe Microscopy Modeling Molecular Organelles Pathway interactions Phenotype Physicians Physiological Reader Regulatory Pathway Reporter Reporting Research Personnel S phase Scientist Sexually Transmitted Diseases Signal Transduction Small Interfering RNA Surface Testing Time Virus aurora kinase A genital infection human pathogen inhibitor metaplastic cell transformation novel novel therapeutic intervention pathogen prevent reproductive tract response

项目摘要

Project Summary/Abstract More than 1.7 million cases of Chlamydia trachomatis infections are reported to the CDC each year, making it the most commonly reported infectious disease in the country. C. trachomatis causes an intracellular infection, and we have discovered that this bacterium causes two effects on an infected host cell that have not been previously described: 1) loss of the primary cilium, which is a solitary surface projection on most differentiated cells in the body; 2) re-entry of a quiescent host cell into the cell cycle. These novel host-pathogen interactions may have been missed because the conventional Chlamydia cell culture infection model uses cycling cells that lack primary cilia. In Aim 1, we will determine if Chlamydia infection causes loss of the primary cilium by inducing cilia disassembly through the AurA regulatory pathway of the host cell. In Aim 2, we will investigate how Chlamydia causes cell cycle re-entry and will determine if the infection involves and dysregulates known cellular regulators of cell cycle re-entry and progression. In Aim 3, we will study if and how Chlamydia-induced primary cilia loss and cell cycle re-entry promote the chlamydial infection. We will also investigate if these two host-pathogen interaction are functionally linked or independent from each other. Successful completion of these studies will define two novel host-pathogen interactions: no microbe is known to cause primary cilia loss, and only viruses, but not bacteria, have been shown to cause quiescent host cells to re-enter the cell cycle. Interventions to prevent Chlamydia-induced primary cilia loss and cell cycle re-entry may lead to a novel therapeutic strategy against Chlamydia infections.

项目概要/摘要已报告超过 170 万例沙眼衣原体感染病例疾病预防控制中心每年都会报告这种疾病，使其成为该国最常报告的传染病。沙眼衣原体引起细胞内感染，我们发现这细菌对受感染的宿主细胞造成两种以前从未发生过的影响描述：1）初级纤毛丧失，初级纤毛是大多数人身上的一个单独的表面投影体内已分化的细胞； 2）休眠宿主细胞重新进入细胞周期。这些新的宿主-病原体相互作用可能被忽略了，因为传统的衣原体细胞培养感染模型使用缺乏原代细胞的循环细胞纤毛。在目标 1 中，我们将确定衣原体感染是否导致初级纤毛丢失通过宿主细胞的 AurA 调节途径诱导纤毛解体。在目标 2，我们将研究衣原体如何导致细胞周期重新进入，并确定是否感染涉及细胞周期再进入的已知细胞调节因子并使其失调和进展。在目标 3 中，我们将研究衣原体是否以及如何诱导初级纤毛丢失细胞周期重新进入促进衣原体感染。我们还将调查这些是否两种宿主-病原体相互作用在功能上相互关联或相互独立。这些研究的成功完成将定义两种新型的宿主-病原体相互作用：目前还没有已知的微生物会导致初级纤毛损失，并且只有病毒而不是细菌会导致原发性纤毛损失。已被证明可以导致休眠的宿主细胞重新进入细胞周期。干预措施防止衣原体诱导的初级纤毛丢失和细胞周期重新进入可能会导致一种新的针对衣原体感染的治疗策略。