GAIT complex formation and Mycobacterium tuberculosis
步态复合体的形成和结核分枝杆菌
基本信息
- 批准号:10195661
- 负责人:
- 金额:$ 24.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-01 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAmino Acyl-tRNA SynthetasesAnti-Inflammatory AgentsAntibodiesAntimycobacterial AgentsBacillusBindingBiologicalCCL11 geneCCL22 geneCCL25 geneCDK5 geneCDK6-associated protein p18CXCL13 geneCell LineCellsCeruloplasminComplementComplexCyclic GMP-Dependent Protein KinasesDataDetectionDrug resistance in tuberculosisElementsEnvironmentEtiologyExposure toGenus MycobacteriumGoalsGrowthHealthHumanImmune responseImmune systemImmunoprecipitationInfectionInflammationInflammatoryInterferon Type IIInterferon-alphaInvadedKineticsMacrophage ActivationMacrophage Colony-Stimulating FactorMeasuresMediatingMessenger RNAMicrobeModelingMolecularMonitorMycobacterium InfectionsMycobacterium bovisMycobacterium tuberculosisMycobacterium tuberculosis H37RvNatural ImmunityOutcomePathogenesisPathogenicityPeripheral Blood Mononuclear CellPhagocytosisPhagosomesPharmacologic SubstancePhosphorylationPhosphotransferasesPlanet EarthPopulationProcessProtein InhibitionProtein KinaseProtein SubunitsProteinsReactionRibosomal ProteinsRibosomesRoleSystemT-LymphocyteTestingTranslationsTuberculosisU937 CellsUntranslated RegionsVEGFA geneVirulenceWestern BlottingWorld Health OrganizationantimicrobialbactericidecGMP-dependent protein kinase Ibetachemokinecytokinedesignexperimental studyinhibitor/antagonistmacrophagemimeticsmonocytemutantmycobacterialnovelnovel therapeutic interventionp38 Mitogen Activated Protein Kinasepathogenpreventprolylglutamic acidreceptorresistance mechanismresponsesuccess
项目摘要
PROJECT SUMMARY
Tuberculosis (TB) remains a major health concern, especially with the global emergence of drug resistant
Mycobacterium tuberculosis (Mtb) strains. The World Health Organization estimated that nearly one third of the
world's population is currently infected with Mtb, making this bacillus one of the most successful pathogens on
earth. A key factor that contributes to the success of Mtb is its ability to survive inside macrophage, the host
cell that has evolved the ability to capture and kill invading microbes. Following phagocytosis, Mtb must
continuously monitor and appropriately respond to host bactericidal activities in order to establish a safe haven
inside the macrophage's phagosome. The process by which Mtb survive inside macrophages is complex and
still poorly understood. In this application, we propose to study a novel virulence mechanism by which Mtb
hijacks the Interferon Gamma Activated Inhibitor of Translation (GAIT), a translational regulatory mechanism
normally triggered in human macrophages by host kinases to prevent excessive reactions to interferon-gamma
(IFNγ), a pro-inflammatory cytokine produced by T cells to activate antimicrobial activities in macrophages. Our
preliminary data support the hypothesis that the eukaryotic-type Ser/Thr protein kinase G (PknG) from Mtb
affects the phosphorylation status of the 60S-ribosomal subunit protein L13a, and the Glu/Pro-tRNA
synthetase, EPRS, leading to the assembly of GAIT in an IFNγ-independent manner. Experiments in Specific
Aim 1 are aimed to determine (i) the kinetics of GAIT assembly in response to mycobacterial infection, (ii) the
role of PknG in Mtb-induced GAIT assembly and (iii) the impact of PknG kinase activity on Mtb growth inside
human primary macrophages. Furthermore, experiments in Specific Aim 2 are designed to assess the impact
of Mtb's PknG-induced GAIT assembly on the bacillus' intracellular survival. Together, these proposed
experiments will elucidate the biological relevance of GAIT assembly for Mtb's survival in human
macrophages, and establish the biological importance of Mtb's ability, through its PknG, to hijack GAIT
assembly. This molecular tactic may allow Mtb to render the macrophage intracellular environment less anti-
inflammatory and antimycobacterial, to promote its own survival. Understanding such an important virulence
mechanism may help to develop novel therapeutic strategies that boost the innate anti-Mtb activities of our
immune system.
项目摘要
结核病(TB)仍然是一个主要的健康问题,特别是随着全球抗药性结核病的出现,
结核分枝杆菌(Mtb)菌株。世界卫生组织估计,近三分之一的
世界人口目前感染了结核分枝杆菌,使这种杆菌成为最成功的病原体之一,
地球导致结核分枝杆菌成功的一个关键因素是它在宿主巨噬细胞内存活的能力
这种细胞已经进化出捕获和杀死入侵微生物的能力。在吞噬作用之后,Mtb必须
持续监测并适当应对宿主的杀菌活动,以建立安全的避风港
在巨噬细胞的吞噬体内结核分枝杆菌在巨噬细胞内存活的过程是复杂的,
仍然知之甚少。在本申请中,我们提出研究一种新的毒力机制,
劫持干扰素γ激活的翻译抑制剂(GAIT),一种翻译调节机制
通常在人巨噬细胞中由宿主激酶触发,以防止对干扰素-γ的过度反应
(IFNγ),一种由T细胞产生以激活巨噬细胞中的抗微生物活性的促炎细胞因子。我们
初步的数据支持这一假设,即来自结核分枝杆菌的真核型Ser/Thr蛋白激酶G(PknG)
影响60 S-核糖体亚基蛋白L13 a和Glu/Pro-tRNA的磷酸化状态
合成酶EPRS,导致GAIT以不依赖于IFNγ的方式组装。具体实验
目的1旨在确定(i)响应于分枝杆菌感染的GAIT组装的动力学,(ii)响应于分枝杆菌感染的GAIT组装的动力学。
PknG在Mtb诱导的GAIT组装中的作用和(iii)PknG激酶活性对Mtb内生长的影响
人原代巨噬细胞。此外,具体目标2中的实验旨在评估影响
Mtb的PknG诱导的GAIT组装对芽孢杆菌细胞内存活的影响。总之,这些建议
实验将阐明GAIT组装对Mtb在人类中存活的生物学相关性
巨噬细胞,并建立Mtb的能力的生物学重要性,通过其PknG,劫持GAIT
组装件.这种分子策略可能允许Mtb使巨噬细胞细胞内环境的抗-
炎症和抗分枝杆菌,以促进其自身的生存。了解如此重要的毒力
这一机制可能有助于开发新的治疗策略,提高我们的先天性抗Mtb活性。
免疫系统
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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Liem Duy Nguyen其他文献
Liem Duy Nguyen的其他文献
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{{ truncateString('Liem Duy Nguyen', 18)}}的其他基金
GAIT complex formation and Mycobacterium tuberculosis
步态复合体的形成和结核分枝杆菌
- 批准号:
10381691 - 财政年份:2021
- 资助金额:
$ 24.15万 - 项目类别:
A Novel Folate Antagonistic Strategy to Treat Drug Resistant Pseudomonas aeruginosa and Enterobacteriaceae
治疗耐药铜绿假单胞菌和肠杆菌的新型叶酸拮抗策略
- 批准号:
8956026 - 财政年份:2015
- 资助金额:
$ 24.15万 - 项目类别:
Folate Metabolism in Mycobacterium tuberculosis Revisited: A Potential Drug Targe
重新审视结核分枝杆菌中的叶酸代谢:潜在的药物目标
- 批准号:
8636391 - 财政年份:2010
- 资助金额:
$ 24.15万 - 项目类别:
Folate Metabolism in Mycobacterium tuberculosis Revisited: A Potential Drug Targe
重新审视结核分枝杆菌中的叶酸代谢:潜在的药物目标
- 批准号:
7862191 - 财政年份:2010
- 资助金额:
$ 24.15万 - 项目类别:
Folate Metabolism in Mycobacterium tuberculosis Revisited: A Potential Drug Targe
重新审视结核分枝杆菌中的叶酸代谢:潜在的药物目标
- 批准号:
8063151 - 财政年份:2010
- 资助金额:
$ 24.15万 - 项目类别:
Folate Metabolism in Mycobacterium tuberculosis Revisited: A Potential Drug Targe
重新审视结核分枝杆菌中的叶酸代谢:潜在的药物目标
- 批准号:
8445317 - 财政年份:2010
- 资助金额:
$ 24.15万 - 项目类别:
Folate Metabolism in Mycobacterium tuberculosis Revisited: A Potential Drug Targe
重新审视结核分枝杆菌中的叶酸代谢:潜在的药物目标
- 批准号:
8240410 - 财政年份:2010
- 资助金额:
$ 24.15万 - 项目类别:
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