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:10330555
- 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
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:
10084250 - 财政年份:2015
- 资助金额:
$ 49.11万 - 项目类别:
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