Listeria monocytogenes physiology and host pathogen interactions
单核细胞增生李斯特氏菌生理学和宿主病原体相互作用
基本信息
- 批准号:10084250
- 负责人:
- 金额:$ 49.11万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-02-01 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:4 hydroxynonenalActinsAdenosine MonophosphateAffinityAldehydesAntimicrobial EffectAntimicrobial ResistanceBacteriaBacterial InfectionsBindingBiochemicalBiological Response ModifiersBone MarrowCellsCytosolDetectionDiseaseDissectionEnzymesEukaryotic CellExhibitsExposure toFundingGallbladderGenesGeneticGenetic TranscriptionGenetic studyGleanGrantGrowthHealthHost DefenseHumanImmuneImmune responseIn VitroIndividualInfectionInflammationInflammatory ResponseInnate Immune ResponseInnate Immune SystemListeria monocytogenesMediatingMediator of activation proteinMembrane Transport ProteinsModelingMolecularMusNF-kappa BNFKB Signaling PathwayNitric OxideNitric Oxide SynthaseNucleotidesOrganismPathogenesisPattern recognition receptorPeriodicityPhysiologyPredispositionProcessProductionProteinsPublic HealthReactive Nitrogen SpeciesResistanceRoleSecond Messenger SystemsSignal TransductionTestingToxic effectVirulenceWhole Organism Analysisantimicrobialbasecell motilityfitnessfoodbornefoodborne illnessgenome-widehuman pathogenimmune activationin vivoinsightmacrophagemicrobialmouse modelnovelpathogenpathogenic bacteriapolymerizationresistance factorsresistance mechanismresponsetissue culturetooltransmission processtransposon sequencing
项目摘要
ABSTRACT
Listeria monocytogenes is a gram-positive, opportunistic, intracellular bacterial pathogen that causes food borne
illness. Given its well-characterized infection cycle and genetic amenability, L. monocytogenes provides a
powerful tool to interrogate the fundamental aspects of intracellular bacterial pathogenesis and the host immune
response to invasion by intracellular pathogens. L. monocytogenes that enter into the host cell cytosol secrete
the second messenger signaling nucleotide, c-di-AMP, resulting in innate immune activation by the host cell. We
recently identified the host protein RECON as a key mediator of this response. RECON is an enzyme whose
activity is inhibited by c-di-AMP. C-di-AMP inhibition of RECON results in the accumulation of the ROS byproduct
4-hydroxy-2-nonenal (4-HNE), which augments NF-kB activation, resulting in elevated nitric oxide synthase
expression and NO production during infection. Intriguingly, we have revealed that NO produced by the host cell
promotes L. monocytogenes intracellular motility, rather than restricting bacterial growth, and that L.
monocytogenes exhibits extreme NO resistance. Additionally, preliminary studies have revealed that 4-HNE is
ubiquitously induced by eukaryotic cells following exposure to bacteria and that this reactive aldehyde exhibits
antimicrobial effects on bacteria analogous to NO. Furthermore, L. monocytogenes exhibits extreme resistance
to the antimicrobial effects of 4-HNE and induces a specific transcriptional response to 4-HNE exposure, which
we hypothesize promotes survival within the infected host. We have begun in vitro biochemical studies, in vivo
forward genetic studies, and the murine models of infection to interrogate the mechanisms by which L.
monocytogenes counteracts the antimicrobial effects of NO and 4-HNE and utilizes NO to promote virulence. In
Aim I, we will interrogate the mechanisms used by L. monocytogenes to detoxify and counteract the antimicrobial
effects of 4-HNE. In Aim II, we propose to detail the molecular mechanisms of NO resistance and the impacts
on bacterial virulence. Finally, in Aim III we will detail the mechanism of NO induced L. monocytogenes actin-
based motility and explore the in vivo impacts of this process on bacterial invasion and dissemination. Together
these studies will define the molecular mechanisms of exquisite antimicrobial innate immune responses
employed by L. monocytogenes to promote survival within the eukaryotic host.
.
摘要
单核细胞增生李斯特菌是一种革兰氏阳性、机会性、胞内细菌病原体,
病鉴于其良好的特征感染周期和遗传的顺从性,L。单核细胞增多症提供了
一个强大的工具,询问细胞内细菌发病机制和宿主免疫的基本方面
对细胞内病原体入侵的反应。L.进入宿主细胞胞质溶胶的单核细胞增多症
第二信使信号核苷酸,c-di-AMP,导致宿主细胞的先天免疫激活。我们
最近确定了宿主蛋白RECON作为这种反应的关键介质。RECON是一种酶,
活性被c-di-AMP抑制。RECON的C-di-AMP抑制导致ROS副产物的积累
4-羟基-2-壬烯醛(4-HNE),增强NF-κ B活化,导致一氧化氮合酶升高
表达和NO的产生。有趣的是,我们已经发现,由宿主细胞产生的NO
促进L.单核细胞增多症的细胞内运动,而不是限制细菌的生长,和L。
单核细胞增多症表现出极端的NO抗性。此外,初步研究表明,4-HNE是
在暴露于细菌后由真核细胞普遍诱导,并且这种反应性醛表现出
对NO类似菌的抑菌作用。单核细胞增多症表现出极强的抵抗力
对4-HNE的抗菌作用,并诱导对4-HNE暴露的特异性转录反应,
我们假设它能促进受感染宿主的存活。我们已经开始了体外生物化学研究,
进一步的遗传学研究,以及小鼠感染模型来询问L.
单核细胞增多症抵消NO和4-HNE的抗微生物作用,并利用NO来提高毒力。在
目的一,我们将询问L使用的机制。单核细胞增多症解毒和抵消抗菌
4-HNE的影响。在目标II中,我们建议详细说明NO抗性的分子机制以及
关于细菌毒性的研究最后,在目的III中,我们将详细介绍NO诱导L.单核细胞增生肌动蛋白
的运动性,并探讨这一过程对细菌入侵和传播的体内影响。一起
这些研究将确定精确的抗菌先天免疫反应的分子机制
L的工作。单核细胞增多症以促进真核宿主内的存活。
.
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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Joshua Woodward其他文献
Joshua Woodward的其他文献
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{{ truncateString('Joshua Woodward', 18)}}的其他基金
Kvbeta2 and the host response to cyclic dinucleotides
Kvbeta2 和宿主对环状二核苷酸的反应
- 批准号:
10188906 - 财政年份:2021
- 资助金额:
$ 49.11万 - 项目类别:
Kvbeta2 and the host response to cyclic dinucleotides
Kvbeta2 和宿主对环状二核苷酸的反应
- 批准号:
10358622 - 财政年份:2021
- 资助金额:
$ 49.11万 - 项目类别:
FRET based imaging of cyclic dinucleotide dynamics in living systems
基于 FRET 的生命系统中环状二核苷酸动力学成像
- 批准号:
10038738 - 财政年份:2020
- 资助金额:
$ 49.11万 - 项目类别:
FRET based imaging of cyclic dinucleotide dynamics in living systems
基于 FRET 的生命系统中环状二核苷酸动力学成像
- 批准号:
10183159 - 财政年份:2020
- 资助金额:
$ 49.11万 - 项目类别:
The mechanisms of 4-HNE mediated host-microbe interactionsdline
4-HNE介导的宿主-微生物相互作用的机制
- 批准号:
9397512 - 财政年份:2016
- 资助金额:
$ 49.11万 - 项目类别:
The mechanisms of 4-HNE mediated host-microbe interactionsdline
4-HNE介导的宿主-微生物相互作用的机制
- 批准号:
9221802 - 财政年份:2016
- 资助金额:
$ 49.11万 - 项目类别:
Listeria monocytogenes physiology and host pathogen interactions
单核细胞增生李斯特氏菌生理学和宿主病原体相互作用
- 批准号:
10330555 - 财政年份:2015
- 资助金额:
$ 49.11万 - 项目类别:
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