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Functional characterization of Chlamydia trachomatis inclusion membrane proteins and their role in subversion of host vesicular trafficking

沙眼衣原体包涵膜蛋白的功能特征及其在破坏宿主囊泡运输中的作用

基本信息

批准号：
10363758
负责人：
Mary Weber
金额：
$ 44.45万
依托单位：
UNIVERSITY OF IOWA
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：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10363758
关键词：
Address Animals Antibiotics Bacteria Bacterial Infections Bacterial Proteins Binding Blindness Cell Culture Techniques Cells Ceramides Chlamydia Chlamydia Infections Chlamydia trachomatis Complex Data Defect Development Disease Ectopic Pregnancy Endosomes Etiology Genetic Goals Golgi Apparatus Growth Impairment Incidence Infection Infertility Integration Host Factors Iron Knowledge Label Lipids Mediating Membrane Membrane Proteins Metabolic Microtubules Molecular Nutrient Organelles Paper Pathogenesis Pathway interactions Pelvic Inflammatory Disease Positioning Attribute Prevalence Process Proteins Recurrence Recycling Reporting Role SNAP receptor Sexual Transmission Sexually Transmitted Diseases Source Techniques Therapeutic Intervention Trachoma Transferrin Vacuole Vesicle Work base genetic manipulation global health insight new therapeutic target novel therapeutic intervention pathogen rab GTP-Binding Proteins recruit trafficking trans-Golgi Network vesicle transport

项目摘要

Project Summary Chlamydia trachomatis (C.t.) is the leading cause of non-congenital blindness and the most prevalent sexually transmitted bacterial infection in the world and thus, has a major impact on global health. C.t. replicates in a membrane-bound vacuole, termed the inclusion, that is extensively modified early in infection through the incorporation of over 50 type III secreted effector proteins termed inclusion membrane proteins (Incs). From within the confines of the inclusion, the bacterium must engage select host organelles to obtain key nutrients such as lipids and iron for bacterial replication and inclusion expansion. Despite the importance of nutrient acquisition to chlamydial infection, a major gap in our knowledge exists regarding how C.t. acquires these essential substrates from the host cell. Recent work from our group shows that the Inc protein CT229 binds and recruits Rab GTPases and specific Rab effectors to the inclusion. Using cutting-edge genetics, we showed that the absence of CT229 results in defects in intracellular replication and inclusion development. We hypothesize that CT229-Rab interactions direct post-Golgi vesicles and recycling endosomes to the inclusion for the acquisition of essential substrates needed for proliferation and inclusion expansion. In Aim 1, we will determine how CT229-Rab interactions promote lipid acquisition by hijacking host vesicular trafficking pathways and iron acquisition by promoting the recruitment of transferrin-positive vesicles to the inclusion. We will evaluate the lipid composition of the bacterial and inclusion membranes and evaluate the importance of lipid acquisition for incorporation into the inclusion and bacterial membranes. We will also answer a major long-standing question in the field by determining whether transferrin indeed serves as a major source of iron for chlamydia and furthermore mechanistically probe the mechanisms by which chlamydia may extract iron from this pathway. It is unlikely that CT229 alone controls vesicle hijacking from start to finish, therefore in Aim 2 we will identify the complex of host and bacterial proteins that are formed at the inclusion during CT229-Rab interactions. Using cellular, genetic, and molecular techniques we will evaluate the impact of Inc-Inc interactions on Rab-dependent vesicle transport to the inclusion. Detailed characterization of the bacterial and host proteins that co-opt host vesicular trafficking during C.t. infection will provide a holistic view of how intracellular pathogens coordinate the capture and fusion of host vesicles that are necessary for bacterial infection.

项目总结