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How chlamydia generates cytoskeletal scaffolds and their role during infection

衣原体如何产生细胞骨架支架及其在感染过程中的作用

基本信息

批准号：
10539241
负责人：
FABIENNE Michelle PAUMET
金额：
$ 39万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-22 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10539241
关键词：
Actins Bacteria Bacterial Sexually Transmitted Diseases Binding Biological Blindness CRISPR/Cas technology Cells Chlamydia Chlamydia Infections Chlamydia trachomatis Cytoskeletal Modeling Cytoskeletal Proteins Cytoskeleton Data Development Disease Progression Elements Endoplasmic Reticulum Event Face Goals Golgi Apparatus Growth Guanosine Triphosphate Phosphohydrolases Immunoprecipitation Infection Knock-out Knowledge Life Cycle Stages Life Style Lipids Malignant Neoplasms Malignant neoplasm of cervix uteri Malignant neoplasm of ovary Mass Spectrum Analysis Mediating Membrane Membrane Proteins Microtubule Stabilization Microtubules Modeling Molecular Multivesicular Body Nutrient Organelles Pathogenesis Pathway interactions Play Polymers Positioning Attribute Prevalence Productivity Proteins Research Risk Role Salmonella Sexually Transmitted Diseases Structure System Testing Therapeutic Transfection Western Blotting bacterial fitness cancer risk fitness human pathogen infection rate insight isophosphamide mustard novel pathogen polymerization recruit scaffold tool tumor progression

项目摘要

PROJECT SUMMARY The intracellular bacterium Chlamydia trachomatis is a major cause of sexually transmitted disease and infectious blindness with over 150 million cases worldwide. Once inside the cell, Chlamydia replicates in a parasitic compartment called an inclusion, which is encased in actin and microtubules scaffolds. Actin scaffolds provide inclusion integrity, while microtubules (MT) control Golgi repositioning around the inclusion; both of these events are necessary for Chlamydia survival. Despite the importance of cytoskeleton rearrangements for Chlamydia's life cycle, a major gap exists regarding the molecular mechanism used by this bacterium to control the cytoskeleton. Furthermore, Chlamydia redirects multiple host organelles to its inclusion during infection. Remarkably, which cytoskeleton scaffold controls this repositioning remains to be identified. Of note, this is a key question as organelle repositioning enhances lipid and nutrient transfer to the inclusion, which then contribute to the growth of the inclusion membrane and the replication of the bacteria. Using recently established genetically-modified Chlamydia strains, we propose to study the role of novel chlamydial proteins (also called effectors) in the formation of cytoskeleton scaffolds. These effectors have been shown to interact with cytoskeleton proteins in transfected cells and are, therefore, ideal candidates to manipulate cytoskeleton during infection. Specifically, we will test the hypotheses that 1) Chlamydia builds a molecular platform composed of multiple bacterial and host proteins to coordinate actin and MT rearrangements during infection, and 2) as cytoskeletal scaffolds are woven around the inclusion, various organelles are then diverted towards the inclusion to promote Chlamydia's survival. Ultimately, this information will have a broad scientific impact as (i) It will establish the detailed mechanism used by Chlamydia to repurpose two major cytoskeleton elements for its own benefit and will provide a better understanding of disease progression; (ii) Cytoskeleton rearrangement plays a critical role in cancer development. Since Chlamydia infection has been associated with an increased risk of cancer, understanding how the cytoskeleton is reorganized during infection will shed light on this phenomenon; (iii) Understanding the mechanism that controls cytoskeleton dynamics will provide critical insight into fundamental biological pathways, and (iv) Finally, a detailed characterization of the proteins that control cytoskeletal dynamics during Chlamydia infection will provide fundamental tools to screen for the presence of similar effectors in other major human pathogens that also manipulate host cytoskeleton, in particular Salmonella, thus opening new avenues of research in molecular pathogenesis.

项目总结细胞内沙眼衣原体是性传播疾病的主要原因，传染性失明，全世界有超过1.5亿例。一旦进入细胞，衣原体就会在被包裹在肌动蛋白和微管支架中的寄生室称为包涵体。肌动蛋白支架提供包裹体的完整性，而微管(MT)控制包涵体周围高尔基体的重新定位；两者这些事件对于衣原体的生存是必要的。尽管细胞骨架重排对衣原体的生命周期，关于这种细菌用来控制细胞骨架。此外，衣原体在感染期间将多个宿主细胞器重定向到它的包涵体。值得注意的是，控制这种重新定位的是哪种细胞骨架支架，仍有待确定。值得注意的是，这是一个关键问题是细胞器的重新定位增强了脂类和营养物质向包涵体的转移，从而有助于包涵膜的生长和细菌的复制。利用最近建立的转基因衣原体菌株，我们建议研究新的衣原体蛋白(也称为效应物)在细胞骨架支架的形成中起作用。这些效应器已经被被证明与转基因细胞中的细胞骨架蛋白相互作用，因此是理想的候选者在感染过程中操纵细胞骨架。具体地说，我们将检验这样的假设：1)衣原体建立了一种多种细菌和宿主蛋白组成的分子平台协调肌动蛋白和MT 感染期间的重排，以及2)当细胞骨架围绕包涵体编织时，然后，各种细胞器转向包涵体，以促进衣原体的生存。最终，这些信息将产生广泛的科学影响，因为(I)它将建立详细的机制衣原体用来改变两个主要细胞骨架成分的用途，以实现自身的利益，并将提供更好的了解疾病进展；(Ii)细胞骨架重排在癌症中起关键作用发展。由于衣原体感染与癌症风险的增加有关，因此理解细胞骨架在感染期间如何重组将有助于揭示这一现象；(Iii)理解控制细胞骨架动力学的机制将提供对基础生物学的重要洞察途径，以及(Iv)最后，控制细胞骨架动力学的蛋白质的详细特征衣原体感染将为筛查其他主要疾病中是否存在类似效应物提供基本工具也操纵宿主细胞骨架的人类病原体，特别是沙门氏菌，从而开辟了新的途径在分子发病机制方面的研究。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cross Talk between ARF1 and RhoA Coordinates the Formation of Cytoskeletal Scaffolds during Chlamydia Infection.

DOI：
10.1128/mbio.02397-21
发表时间：
2021-12-21
期刊：
mBio
影响因子：
6.4
作者：
Haines A;Wesolowski J;Ryan NM;Monteiro-Brás T;Paumet F
通讯作者：
Paumet F

Chlamydia Hijacks ARF GTPases To Coordinate Microtubule Posttranslational Modifications and Golgi Complex Positioning.

DOI：
10.1128/mbio.02280-16
发表时间：
2017-05-02
期刊：
mBio
影响因子：
6.4
作者：
Wesolowski J;Weber MM;Nawrotek A;Dooley CA;Calderon M;St Croix CM;Hackstadt T;Cherfils J;Paumet F
通讯作者：
Paumet F

Taking control: reorganization of the host cytoskeleton by Chlamydia.

控制：衣原体重组宿主细胞骨架。