Mechanisms of SFG Rickettsia-Host Interactions
Mechanisms of SFG Rickettsia-Host Interactions
批准号:
10468216
负责人:
REBECCA L LAMASON
金额:
$55.82万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-08-12 至 2025-07-31
关键词:
Ankyrin RepeatBacterial InfectionsBacterial ProteinsBiochemicalBiologicalBiological AssayBiologyCell Adhesion MoleculesCell physiologyCell-Cell AdhesionCellsCellular biologyCessation of lifeComplementComplexCytosolDevelopmentDiagnosticEctopic ExpressionExanthemaFutureGenesGeneticGenetic VariationGenetic studyGoalsHumanImpairmentInfectionIntegration Host FactorsIntercellular JunctionsInvadedLabelLaboratoriesLeadLifeLife Cycle StagesLocationMediatingMetabolicMicroscopyModelingModernizationMolecularMutagenesisPathogenesisPathogenicityPathway interactionsPhasePlasmidsPropertyProteinsProteomicsResearchRickettsiaRickettsia InfectionsRickettsia parkeriSiteStructureSystemTechniquesTestingTherapeutic InterventionTick-Borne DiseasesTick-Borne InfectionsTimeType IV Secretion System PathwayUnited States National Institutes of HealthVascular DiseasesVinculinWidespread DiseaseWorkbasecombatdesignforward geneticsgenetic approachgenetic manipulationimprovedinsightinterestmembermutantpathogenpathogenic bacteriapreventspotted fevertargeted treatmenttherapeutic targettick-bornetool
中文摘要
项目摘要/摘要
在美国,由斑点热病引起的一组新出现的、但特征不佳的壁虱传播疾病
群(SFG)立克次体。这些专有的细胞内细菌病原体会导致轻微的甚至危及生命的血管
人类的疾病,诊断和治疗干预措施也很有限。促进广泛传播
疾病,SFG立克次体物种进化出动态策略,入侵宿主细胞,逃逸到细胞质中,
从一个细胞传播到另一个细胞。我们假设SFG立克次体通过传递
分泌的细菌蛋白(即效应器)的武器库,它重新编程宿主细胞的过程。不幸的是,
这些分泌效应器的身份和宿主目标在很大程度上仍不清楚。此外,直接分析
分泌系统和假定的效应器由于在生长和生长中的挑战而受到阻碍
在实验室里对这些病原体进行基因操作。为了克服这一障碍,我们最近向前调整了
对模型SFG成员帕氏立克次体的遗传学和基于质粒的互补,允许
SFG立克次体发病机制的强大功能遗传学研究。使用这些工具,我们发现
分泌型效应子Sca4通过调控宿主细胞与细胞间的黏附,促进细胞间扩散的晚期。
此外,功能未知的分泌型效应器(RARP-1)及其组分的转座子突变
异常的4型立克次体分泌系统(VirB6e)损害帕氏杆菌感染的不同阶段。这
提案将利用这些关键进展来研究分泌系统和分泌效应器如何促进
帕氏杆菌感染生命周期的不同阶段。在这里,我们将我们的功能遗传策略和
在宿主细胞生物学方面的专业知识,以及现代生化技术,以揭示关键的、机械的见解
SFG立克次体发病机制。在目标1中,我们将研究T4SS组件的功能和分泌组
VirB6e。在目标2中,我们将确定分泌的效应物RARP-1如何促进帕氏杆菌感染。在《目标3》中,
我们将阐明Sca4是如何在帕氏杆菌细胞间的过程中特异性地靶向宿主细胞-细胞黏附复合体的。
散开。总的来说,拟议的研究将极大地提高我们对
立克次体生物学和立克次体与宿主的相互作用并揭示预防或治疗扁虱病的治疗靶点
疾病。
英文摘要
PROJECT SUMMARY/ABSTRACT
A subset of emerging, but poorly characterized tickborne diseases in the U.S. are caused by Spotted Fever
Group (SFG) Rickettsia. These obligate intracellular bacterial pathogens cause mild-to-life-threatening vascular
diseases in humans and have a limited set of diagnostics and therapeutic interventions. To promote widespread
disease, SFG Rickettsia species have evolved dynamic strategies to invade host cells, escape into the cytosol,
and spread from cell to cell. We hypothesize that SFG Rickettsia coordinate their complex life cycle by delivering
an arsenal of secreted bacterial proteins (i.e., effectors) that reprogram host cell processes. Unfortunately, the
identity and host targets of these secreted effectors have remained largely unknown. Furthermore, direct analysis
of the secretion systems and putative effectors have been hampered due to challenges in growing and
genetically manipulating these pathogens in the lab. To overcome this barrier, we recently adapted forward
genetics and plasmid-based complementation to the model SFG member Rickettsia parkeri, allowing for
powerful functional-genetic studies of SFG Rickettsia pathogenesis. Using these tools, we discovered that the
secreted effector Sca4 promotes a late stage of cell-to-cell spread by manipulating host cell-cell adhesion.
Additionally, transposon mutagenesis of a secreted effector of unknown function (RARP-1) and a component of
the anomalous Rickettsia Type 4 secretion system (VirB6e) impairs distinct stages of R. parkeri infection. This
proposal will leverage these key advances to examine how a secretion system and secreted effectors promote
different steps of the R. parkeri infectious life cycle. Here, we combine our functional-genetic strategies and
expertise in host cell biology, with modern biochemical techniques to reveal critical, mechanistic insights into
SFG Rickettsia pathogenesis. In Aim 1, we will examine the function and secretome of the T4SS component
VirB6e. In Aim 2, we will determine how the secreted effector RARP-1 promotes R. parkeri infection. In Aim 3,
we will elucidate how Sca4 specifically targets host cell-cell adhesion complexes during R. parkeri cell-to-cell
spread. Collectively, the proposed research will dramatically improve our fundamental understanding of
Rickettsia biology and Rickettsia-host interactions and reveal therapeutic targets to prevent or treat tickborne
diseases.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Microbial Control of Host Intercellular Communication
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批准号:10363966
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项目类别:
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资助金额:$30.5万
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财政年份:2022
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负责人:REBECCA L LAMASON
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依托单位:
Microbial Control of Host Intercellular Communication
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批准号:10661500
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项目类别:
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资助金额:$30.56万
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财政年份:2022
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负责人:REBECCA L LAMASON
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依托单位:
Mechanisms of SFG Rickettsia-Host Interactions
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批准号:10293664
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项目类别:
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资助金额:$55.82万
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财政年份:2021
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负责人:REBECCA L LAMASON
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依托单位:
Mechanisms of SFG Rickettsia-Host Interactions
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批准号:10651764
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资助金额:$55.82万
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依托单位:
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依托单位:
Regulation of CARD11 by a kinesin-like protein, GAKIN
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批准号:7505435
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项目类别:
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资助金额:$3.46万
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财政年份:2007
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负责人:REBECCA L LAMASON
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依托单位:
Regulation of CARD11 by a kinesin-like protein, GAKIN
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批准号:7406429
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项目类别:
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资助金额:$3.46万
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财政年份:2007
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负责人:REBECCA L LAMASON
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依托单位:
海外基金