Functional characterization of early Chlamydia effectors
早期衣原体效应器的功能特征
基本信息
- 批准号:10406259
- 负责人:
- 金额:$ 46.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-06-01 至 2023-11-30
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelBacteriaBindingCell Culture TechniquesCellsChlamydiaChlamydia InfectionsChlamydia trachomatisChronicEpithelialF-ActinGeneticGoalsImmune signalingImpairmentInfectionInfertilityInflammationInnate Immune ResponseIntercellular JunctionsInterferon Type ILeadMammalian CellMediatingMembraneModificationMolecularMolecular GeneticsMorbidity - disease rateMutationPathogenicityPathologyPelvic Inflammatory DiseasePhosphatidylinositolsPhosphotransferasesPlayProcessProteinsProteomicsRegulationReproductive HealthResearchRoleSexual TransmissionSignal PathwaySignal TransductionSurfaceSystemTestingTherapeutic InterventionTissuesVacuoleVirulence FactorsWomanWorkfunctional groupin vivomutantnovelpathogenpublic health relevanceresponsetargeted treatmenttoolurogenital tract
项目摘要
Project Description/Summary/Abstract
The obligate intracellular bacterium Chlamydia trachomatis is a widely disseminated obligate
pathogen that infects epithelial surfaces of the urogenital tract, leading to severe sequela such as pelvic
inflammatory disease, and infertility. During the initial stages of infection Chlamydia likely delivers
between 10-15 separate Type III secreted (T3S) “effector” proteins into the target host cell. We
hypothesize that these Chlamydia effector proteins work co-operatively to temporally reprogram
signaling pathways and cytoskeletal functions to promote cell invasion and establish a nascent
pathogenic vacuole (“inclusion”)
In our first aim, we propose to apply emerging genetic and molecular genetic tools in Chlamydia to
define the role of early effectors play in invasion, inclusion maturation and in vivo infections. We also
propose to perform an epistatic analysis of combinations of effector mutants to group effector by
functional groups and to prioritize a detailed molecular characterization of effector that are central
signaling nodes.
In our second aim, we focus on the characterization of Tepp, an effector that plays important roles
in reprograming signaling pathways, including those involved in innate immune responses. We propose
to define the mechanism of activation of Class I phosphoinositide 3 kinases (PI3K) at nascent
inclusions and the role these activities play in the regulation of membrane dynamics and activation of
Type I interferon responses. In parallel, we will identify the molecular players that lead to the Tepp-
mediated activation and modification of Eps8, a regulator of Rac1 activity and cell-cell junctions, by
applying “proximity proteomics” approaches.
Overall, our research plan seeks to perform both a systems levels assessment of the function of
early effectors and a detailed molecular characterization of mechanism of action for selected effectors.
The overall goal is to define the molecular basis of how specific effector(s) function, identify how
signaling pathways are re-programmed and how they all ultimately contribute to Chlamydia survival in
host tissues and the induction of pathology.
项目描述/摘要/摘要
专性胞内细菌沙眼衣原体是一种广泛传播的专性细菌。
病原体感染泌尿生殖道上皮表面,导致盆腔等严重后遗症
在感染的最初阶段,衣原体可能会传播炎症性疾病和不孕症。
10-15 个独立的 III 型分泌 (T3S)“效应”蛋白进入目标宿主细胞。
研究发现这些衣原体效应蛋白协同工作以暂时重新编程
信号通路和细胞骨架功能促进细胞侵袭并建立新生细胞
致病性真空(“包容性”)
在我们的第一个目标中,我们建议将新兴的衣原体遗传和分子遗传工具应用于
我们还定义了早期效应器在侵袭、包涵体成熟和体内感染中的作用。
提议对效应突变体组合进行上位分析,以分组效应
官能团并优先考虑核心效应子的详细分子特征
信令节点。
在我们的第二个目标中,我们重点关注 Tepp 的特征,Tepp 是一个发挥重要作用的效应器
我们建议重新编程信号通路,包括那些涉及先天免疫反应的信号通路。
定义 I 类磷酸肌醇 3 激酶 (PI3K) 在新生阶段的激活机制
内含物以及这些活性在膜动力学调节和激活中发挥的作用
同时,我们将确定导致 Tepp- 的分子参与者。
介导 Eps8 的激活和修饰,Eps8 是 Rac1 活性和细胞-细胞连接的调节因子
应用“邻近蛋白质组学”方法。
总体而言,我们的研究计划旨在对功能进行系统级别的评估
早期效应器和所选效应器作用机制的详细分子特征。
总体目标是定义特定效应器如何发挥作用的分子基础,确定如何
信号通路被重新编程,以及它们最终如何促进衣原体的存活
宿主组织和病理学的诱导。
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A renewed tool kit to explore Chlamydia pathogenesis: from molecular genetics to new infection models.
- DOI:10.12688/f1000research.18832.1
- 发表时间:2019-01-01
- 期刊:
- 影响因子:0
- 作者:Dolat, Lee;Valdivia, Raphael H
- 通讯作者:Valdivia, Raphael H
The acetylase activity of Cdu1 regulates bacterial exit from infected cells by protecting Chlamydia effectors from degradation.
Cdu1 的乙酰化酶活性通过保护衣原体效应子免遭降解来调节细菌从受感染细胞中排出。
- DOI:10.1101/2023.02.28.530337
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Bastidas,RobertJ;Kędzior,Mateusz;Davidson,RobertK;Walsh,StephenC;Dolat,Lee;Sixt,BarbaraS;Pruneda,JonathanN;Coers,Jörn;Valdivia,RaphaelH
- 通讯作者:Valdivia,RaphaelH
Chlamydia repurposes the actin-binding protein EPS8 to disassemble epithelial tight junctions and promote infection.
- DOI:10.1016/j.chom.2022.10.013
- 发表时间:2022-12-14
- 期刊:
- 影响因子:30.3
- 作者:Dolat, Lee;Carpenter, Victoria K.;Chen, Yi-Shan;Suzuki, Michitaka;Smith, Erin P.;Kuddar, Ozge;Valdivia, Raphael H.
- 通讯作者:Valdivia, Raphael H.
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Raphael H Valdivia其他文献
Raphael H Valdivia的其他文献
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{{ truncateString('Raphael H Valdivia', 18)}}的其他基金
A spatial transcriptional analsysis of Chlamydia-mediated upper genital tract pathology
衣原体介导的上生殖道病理学的空间转录分析
- 批准号:
10573583 - 财政年份:2023
- 资助金额:
$ 46.42万 - 项目类别:
2023 Microbial Adhesion and Signal Transduction Gordon Research Conferences and Seminar
2023年微生物粘附和信号转导戈登研究会议和研讨会
- 批准号:
10666171 - 财政年份:2023
- 资助金额:
$ 46.42万 - 项目类别:
Genetic analysis of mucin utilization by Akkermansia muciniphila and its impact on host physiology
阿克曼氏菌利用粘蛋白的遗传分析及其对宿主生理的影响
- 批准号:
9790938 - 财政年份:2018
- 资助金额:
$ 46.42万 - 项目类别:
Genetic analysis of mucin utilization by Akkermansia muciniphila and its impact on host physiology
阿克曼氏菌利用粘蛋白的遗传分析及其对宿主生理的影响
- 批准号:
9652782 - 财政年份:2018
- 资助金额:
$ 46.42万 - 项目类别:
Genetic analysis of mucin utilization by Akkermansia muciniphila and its impact on host physiology
阿克曼氏菌利用粘蛋白的遗传分析及其对宿主生理的影响
- 批准号:
10461766 - 财政年份:2018
- 资助金额:
$ 46.42万 - 项目类别:
Genetic analysis of mucin utilization by Akkermansia muciniphila and its impact on host physiology
阿克曼氏菌利用粘蛋白的遗传分析及其对宿主生理的影响
- 批准号:
10229490 - 财政年份:2018
- 资助金额:
$ 46.42万 - 项目类别:
Functional characterization of early Chlamydia effectors
早期衣原体效应器的功能特征
- 批准号:
10170218 - 财政年份:2018
- 资助金额:
$ 46.42万 - 项目类别:
Structure-Function Analysis of Chlamydia Secretion Chaperones
衣原体分泌伴侣的结构-功能分析
- 批准号:
9211281 - 财政年份:2016
- 资助金额:
$ 46.42万 - 项目类别:
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