Genetic Regulation of the Coxiella burnetii Type IVB Secretion System
伯内特柯克斯体 IVB 型分泌系统的遗传调控
基本信息
- 批准号:8783810
- 负责人:
- 金额:$ 5.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-16 至 2017-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAnimalsBacteriaBacterial TypingBioinformaticsBiologicalBiological AssayBiologyCell LineCellsChronicControlled EnvironmentCoxiellaCoxiella burnetiiDiseaseDomestic AnimalsDominant-Negative MutationEnsureEnvironmentGene ExpressionGene Expression ProfileGene Expression RegulationGenesGeneticGenetic TranscriptionGoalsGrowthHela CellsHost DefenseHumanImmuneImmune responseInfectionInflammatoryInterleukin-1Interleukin-10Interleukin-6LegionellaLysosomesMeasuresMembrane Protein TrafficMessenger RNAMusMutationOperonPathway interactionsPhagosomesPhasePhosphotransferasesPhysiologic pulseProtein SecretionProteinsPublishingQ FeverRNAReactionRegulationRegulonRelative (related person)ReporterResearchSignal TransductionSystemTNF geneTimeType IV Secretion System PathwayVacuoleVariantVirulenceVirulence Factorsdensitymacrophagenext generationpathogenpublic health relevanceresponsesensortooltraffickingtranscriptome sequencing
项目摘要
DESCRIPTION (provided by applicant): Intracellular bacteria rely on secretion systems to modulate the host environment and ensure survival. For Coxiella burnetti, the Type IV secretion system (T4SS) translocates bacterial effector proteins into the host cell, creating a hospitable environment critical for productive infection of host cells. While the T4SS is required for intracellular growth, secretion does not begin until Coxiella have been trafficked to lysosome-like
compartments - suggesting that restriction of secretion benefits the bacterium and that environmental signals provide the impetus for expression of T4SS and its effectors. Coxiella possess only a few two-component systems, including one (QseBC) related to other systems that activate pathogen secretion in response to the host environment. Indeed, a strain with a transposon insertion disrupting the QseBC operon is neither able to secrete a T4BSS effector nor survive within host cells. The specific aims of this proposed research use genetic and cell biological tools to investigate whether the Coxiella QseBC system senses and responds to the maturing phagosome to initiate expression of the T4SS and its effectors. Aim 1 will use a transcriptional profiling and reporter strains to determine the maximal expression of QseB-regulated genes during both axenic and intracellular growth, correlating expression with vacuolar maturation and medium composition to reveal how and when the QseBC system is activated. Aim 2 will use expression of modified QseB proteins to dysregulate T4SS activity and measure inflammatory reaction to secretion in macrophage-like host cells. Together, Aims 1 and 2 will reveal whether temporal and spatial control of secretion enhances Coxiella's ability to evade host defenses, informing our understanding of acute and chronic Q fever infections. Aim 3 will use the information and experimental tools developed during Aims 1 and 2 to intelligently compare mRNA profiles of strains with or without functional QseB. Aim 3 will reveal the full suite of genes regulated by QseB and their relative expression, as well as provide the first whole-transcriptome analysis of Coxiella burnetii. Together, these complementary aims will provide tools to enhance research across the Coxiella field, greatly expand our understanding of Coxiella gene regulation, and suggest fertile avenues for future research into the biology and genetics of an understudied human and animal pathogen.
描述(由申请人提供):细胞内细菌依赖分泌系统调节宿主环境并确保存活。对于贝氏柯克斯体,IV型分泌系统(T4SS)将细菌效应蛋白易位到宿主细胞中,创造了对宿主细胞的生产性感染至关重要的适宜环境。虽然T4 SS是细胞内生长所必需的,但分泌直到柯克斯体被运输到溶酶体样细胞才开始。
这表明限制分泌有益于细菌,并且环境信号为T4SS及其效应物的表达提供动力。柯克斯体只有几个双组分系统,包括一个(QseBC)相关的其他系统,激活病原体分泌响应宿主环境。事实上,具有破坏QseBC操纵子的转座子插入的菌株既不能分泌T4BSS效应子,也不能在宿主细胞内存活。这项研究的具体目的是使用遗传和细胞生物学工具来研究Coxiella QseBC系统是否感知和响应成熟的吞噬体,以启动T4SS及其效应物的表达。目的1将使用转录谱和报告菌株来确定在无菌和细胞内生长期间QseB调节基因的最大表达,将表达与液泡成熟和培养基组成相关联,以揭示QseBC系统如何以及何时被激活。目的2将使用修饰的QseB蛋白的表达来失调T4SS活性并测量巨噬细胞样宿主细胞中对分泌的炎症反应。目标1和2将揭示分泌的时间和空间控制是否增强了Coxiella逃避宿主防御的能力,为我们了解急性和慢性Q热感染提供信息。目标3将使用目标1和2期间开发的信息和实验工具,智能地比较具有或不具有功能性QseB的菌株的mRNA谱。目的3揭示贝氏柯克斯体QseB调控的基因及其相对表达,并首次对贝氏柯克斯体进行全转录组分析。总之,这些互补的目标将提供工具,以加强整个柯克斯体领域的研究,大大扩大我们对柯克斯体基因调控的理解,并为未来研究不足的人类和动物病原体的生物学和遗传学提出肥沃的途径。
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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Shawna Reed其他文献
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{{ truncateString('Shawna Reed', 18)}}的其他基金
Genetic Regulation of the Coxiella burnetii Type IVB Secretion System
伯内特柯克斯体 IVB 型分泌系统的遗传调控
- 批准号:
8928472 - 财政年份:2014
- 资助金额:
$ 5.15万 - 项目类别:
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