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
项目总结/摘要
在美国,一种新出现的、但特征不明显的蜱传疾病是由斑疹热引起的。
组(SFG)立克次体。这些专性细胞内细菌病原体引起轻度至危及生命的血管
人类疾病,并有一套有限的诊断和治疗措施。为促进普遍
疾病时,SFG立克次体物种已经进化出动态策略来侵入宿主细胞,逃逸到胞质溶胶中,
并在细胞间传播我们假设SFG立克次体通过传递
分泌的细菌蛋白质的武库(即,效应子),其重编程宿主细胞过程。可惜
这些分泌的效应物的身份和宿主靶点在很大程度上仍然未知。此外,直接分析
分泌系统和假定的效应器的功能受到阻碍,
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,我们最近进行了调整,
遗传学和质粒为基础的互补模式SFG成员立克次体parkeri,允许
SFG立克次体致病机制的功能遗传学研究。使用这些工具,我们发现,
分泌的效应因子Sca 4通过操纵宿主细胞-细胞粘附促进细胞-细胞扩散的晚期阶段。
此外,功能未知的分泌效应子(RARP-1)和
立克次体4型异常分泌系统(VirB 6 e)损害了R. parkeri感染。这
一项提案将利用这些关键进展来研究分泌系统和分泌的效应物如何促进
R. Parkeri感染性生命周期在这里,我们联合收割机结合我们的功能遗传策略,
在宿主细胞生物学的专业知识,与现代生物化学技术,揭示关键,机械的见解,
SFG立克次体发病机制。在目标1中,我们将研究T4 SS组分的功能和分泌组
VirB6e。在目标2中,我们将确定分泌的效应子RARP-1如何促进R。parkeri感染。在目标3中,
我们将阐明Sca 4在R. parkeri细胞对细胞
传播.总的来说,拟议的研究将大大提高我们对
立克次体生物学和立克次体-宿主相互作用,并揭示预防或治疗蜱传的治疗靶点
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
-
项目类别:
-
资助金额:$30.5万
-
财政年份:2022
-
负责人:REBECCA L LAMASON
-
依托单位:
Microbial Control of Host Intercellular Communication
-
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
-
依托单位:
Mechanisms of SFG Rickettsia-Host Interactions
-
批准号:10293664
-
项目类别:
-
资助金额:$55.82万
-
财政年份:2021
-
负责人:REBECCA L LAMASON
-
依托单位:
Mechanisms of SFG Rickettsia-Host Interactions
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批准号:10651764
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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:
Elucidating how intracellular bacterial pathogens hijack host intercellular communication to promote spread
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批准号:9132279
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项目类别:
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资助金额:$9.0万
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负责人:REBECCA L LAMASON
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依托单位:
Elucidating how intracellular bacterial pathogens hijack host intercellular communication to promote spread
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批准号:9529899
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项目类别:
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资助金额:$24.9万
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财政年份:2015
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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:
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:7671431
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项目类别:
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资助金额:$3.48万
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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