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:10318117
- 负责人:
- 金额:$ 39万
- 依托单位:
- 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 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:ActinsAddressBacteriaBacterial Sexually Transmitted DiseasesBindingBiologicalBlindnessCRISPR/Cas technologyCellsChlamydiaChlamydia InfectionsChlamydia trachomatisCytoskeletal ModelingCytoskeletal ProteinsCytoskeletonDataDevelopmentDisease ProgressionElementsEndoplasmic ReticulumEventFaceGoalsGolgi ApparatusGrowthGuanosine Triphosphate PhosphohydrolasesImmunoprecipitationInfectionKnock-outKnowledgeLife Cycle StagesLife StyleLightLipidsMalignant NeoplasmsMalignant neoplasm of cervix uteriMalignant neoplasm of ovaryMass Spectrum AnalysisMediatingMembraneMembrane ProteinsMicrotubule StabilizationMicrotubulesModelingMolecularMultivesicular BodyNutrientOrganellesPathogenesisPathway interactionsPlayPrevalenceProteinsResearchRiskRoleSalmonellaSexually Transmitted DiseasesStructureSystemTestingTherapeuticWestern Blottingbacterial fitnessbasecancer riskfitnesshuman pathogeninfection rateinsightisophosphamide mustardnovelpathogenpolymerizationrecruitscaffoldtooltumor 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.
项目摘要
细胞内细菌沙眼衣原体是性传播疾病的主要原因,
全世界有超过1.5亿例感染性失明。一旦进入细胞,衣原体就以一种
寄生隔室称为内含物,其被包裹在肌动蛋白和微管支架中。肌动蛋白支架
提供内含物的完整性,而微管(MT)控制高尔基体在内含物周围的重新定位;
这些事件是衣原体生存所必需的。尽管细胞骨架重排对于
衣原体的生命周期,一个主要的差距存在的分子机制,用于控制这种细菌
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其包含体。
值得注意的是,哪种细胞骨架支架控制这种重新定位仍有待确定。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质和营养物质转移到内含物中,然后
有助于包涵体膜的生长和细菌的复制。
使用最近建立的基因修饰衣原体菌株,我们建议研究新的衣原体的作用。
衣原体蛋白(也称为效应物)在细胞骨架支架的形成中起重要作用。这些效应器已经被
显示与转染细胞中的细胞骨架蛋白相互作用,因此是
在感染期间操纵细胞骨架。具体来说,我们将测试假设1)衣原体建立一个
由多种细菌和宿主蛋白组成的分子平台,以协调肌动蛋白和MT
感染期间的重排,和2)由于细胞骨架支架围绕内含物编织,
然后各种细胞器转向包涵体以促进衣原体的存活。
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,
衣原体利用它来重新利用两个主要的细胞骨架元素,使其自身受益,并将提供一个更好的
理解疾病进展;(ii)细胞骨架重排在癌症中起着关键作用
发展由于衣原体感染与癌症风险增加有关,了解
细胞骨架在感染过程中是如何重组的,这将有助于阐明这一现象;(iii)了解
控制细胞骨架动力学的机制将为基础生物学提供重要的见解
途径,和(iv)最后,一个详细的表征蛋白质控制细胞骨架动力学过程中,
衣原体感染将提供基本的工具,以筛选存在类似的效应,在其他主要
人类病原体也操纵宿主细胞骨架,特别是沙门氏菌,从而开辟了新的途径
分子发病机制的研究。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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FABIENNE Michelle PAUMET其他文献
FABIENNE Michelle PAUMET的其他文献
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{{ truncateString('FABIENNE Michelle PAUMET', 18)}}的其他基金
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
- 批准号:
10539241 - 财政年份:2019
- 资助金额:
$ 39万 - 项目类别:
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
- 批准号:
10077785 - 财政年份:2019
- 资助金额:
$ 39万 - 项目类别:
Regulation of membrane fusion in macrophage phagocytosis
巨噬细胞吞噬作用中膜融合的调节
- 批准号:
8683383 - 财政年份:2014
- 资助金额:
$ 39万 - 项目类别:
Regulation of membrane fusion in macrophage phagocytosis
巨噬细胞吞噬作用中膜融合的调节
- 批准号:
8885649 - 财政年份:2014
- 资助金额:
$ 39万 - 项目类别:
How bacteria corrupt the host vesicular trafficking:Role of SNARE-like Proteins
细菌如何破坏宿主囊泡运输:圈套样蛋白的作用
- 批准号:
7872803 - 财政年份:2009
- 资助金额:
$ 39万 - 项目类别:
How bacteria corrupt the host vesicular trafficking:Role of SNARE-like Proteins
细菌如何破坏宿主囊泡运输:圈套样蛋白的作用
- 批准号:
7727695 - 财政年份:2009
- 资助金额:
$ 39万 - 项目类别:
How bacteria corrupt the host vesicular trafficking:Role of SNARE-like Proteins
细菌如何破坏宿主囊泡运输:圈套样蛋白的作用
- 批准号:
8107645 - 财政年份:2009
- 资助金额:
$ 39万 - 项目类别:
How bacteria corrupt the host vesicular trafficking:Role of SNARE-like Proteins
细菌如何破坏宿主囊泡运输:圈套样蛋白的作用
- 批准号:
8288789 - 财政年份:2009
- 资助金额:
$ 39万 - 项目类别:
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