Vibrio cholerae antinitrosative stress defenses and gut microbiome interaction
霍乱弧菌抗亚硝化应激防御和肠道微生物组相互作用
基本信息
- 批准号:10470881
- 负责人:
- 金额:$ 78.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-23 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AdultAffectAnimalsAntibioticsCholeraCholera ToxinCommunitiesComplexCysteineDeveloping CountriesDiarrheaDisease ResistanceDuodenumEnzymesEscherichia coliEtiologyGene ExpressionGenesGenomic IslandsGerm-FreeGoalsGrantGrowthHumanHuman MicrobiomeImmune responseIn VitroInfectionInterventionIslandLactobacillusMetagenomicsMicrobeMicrobial BiofilmsModelingMolecularMorbidity - disease rateMusNOS2A geneNitric OxideNitrogen OxidesOutcomePathogenesisPathogenicityPersonsPoisonPost-Translational Protein ProcessingPredispositionProcessProductionProtein SProteinsProteomicsReactive Nitrogen SpeciesRegulationResearchResistanceRisk FactorsRoleSeriesShapesSiteSmall IntestinesStressStructureTissuesVariantVibrio choleraeVibrio cholerae infectionVirulenceVirulence FactorsWild Type Mouseaminoguanidinebasebiological adaptation to stresschemical propertycommensal microbesdiarrheal diseasedinitrosyl iron complexgastrointestinal functiongut microbesgut microbiomegut microbiotahuman pathogenin vivoinhibitormembermicrobiomemicroorganism interactionmortalitymouse modelnitrosative stressnovelpathogenprophylacticprotective effectresistance mechanismresponsetransposon sequencing
项目摘要
PROJECT SUMMARY
The human pathogen Vibrio cholerae is the etiologic agent of the severe diarrheal disease known as cholera,
which affects millions of people annually, worldwide. In order for V. cholerae to successfully colonize in the
small intestines of the host, it must express a series of virulence factors, which have been the main focus of
the cholera research. However, bacterial pathogenicity is a multifactorial process in vivo that depends not only
on virulence factor expression, but host responses to infection and interactions with the commensal microbes
of the gut, the gut microbiome. One major set of host-produced factors that must be overcome by V. cholerae
comprises nitric oxide (NO) and NO-derived nitrogen oxides and dinitrosyl-iron complexes, collectively known
as nitrosative stress (reactive nitrogen species, RNS). Previous studies show that inducible nitric oxide
synthase (iNOS or NOS2), the enzyme that synthesizes NO, is among the most upregulated proteins in
duodenal tissue during cholera, and our results show both that iNOS is highly induced upon V. cholerae
infection of an adult mouse model, and that V. cholerae colonization is reduced in iNOS-/- mice or mice treated
with the iNOS inhibitor aminoguanidine (AG). However, little is known about how increased RNS in vivo
impacts V. cholerae, the gut microbiome, and the inter-microbial interactions that drive the ultimate outcome of
infection. We hypothesize that RNS production induced during infection modulates the structure, function, and
pathogen interactions of the gut microbiome, granting V. cholerae a competitive advantage over commensals
due to several RNS-resistance mechanisms that are tightly regulated alongside virulence factor expression.
We will examine this hypothesis in two aims. In Aim 1, we will elucidate how V. cholerae responds to RNS
during infection, and how these responses are regulated alongside virulence. In Aim 2, we will examine the
role of RNS in modulating the gut microbiome, how RNS-dependent changes influences V. cholerae
susceptibility, and how RNS affects specific microbial interactions between this pathogen and commensal gut
microbes.
项目总结
人类病原体霍乱弧菌是一种被称为霍乱的严重腹泻疾病的病原体,
每年影响全球数百万人。为了使霍乱弧菌在
在寄主小肠中,它必须表达一系列毒力因子,而这些毒力因子一直是主要关注的焦点
霍乱研究。然而,细菌的致病性在体内是一个多因素的过程,不仅取决于
毒力因子的表达,但宿主对感染的反应以及与共生微生物的相互作用
肠道的微生物群。霍乱弧菌必须克服的一组主要宿主产生的因素
由一氧化氮(NO)和NO衍生的氮氧化物和二亚硝基铁络合物组成,统称为
作为亚硝化胁迫(反应氮物种,RNS)。先前的研究表明,诱导性一氧化氮
合成酶(iNOS或NOS2)是合成NO的酶,是体内最上调的蛋白质之一
霍乱期间的十二指肠组织,我们的结果表明iNOS对霍乱弧菌有很高的诱导作用
成年小鼠模型的感染,以及在iNOS-/-小鼠或经治疗的小鼠中霍乱弧菌定植减少
使用诱导型一氧化氮合酶抑制剂氨基胍(AG)。然而,关于活体内RNS增加的原因还知之甚少
影响霍乱弧菌、肠道微生物群以及推动霍乱最终结果的微生物之间的相互作用
感染。我们假设在感染过程中诱导产生的RNS调节结构、功能和
肠道微生物群的病原体相互作用,使霍乱弧菌具有相对于共生菌的竞争优势
由于RNS的几种抗性机制与毒力因子的表达密切相关。
我们将从两个方面检验这一假说。在目标1中,我们将阐明霍乱弧菌对RNS的反应
在感染过程中,以及这些反应如何与毒力一起调节。在目标2中,我们将研究
RNS在调节肠道微生物群中的作用,RNS依赖的变化如何影响霍乱弧菌
敏感性,以及RNS如何影响病原体和共生肠道之间的特定微生物相互作用
微生物。
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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{{ truncateString('Ansel Hsiao', 18)}}的其他基金
The role of a bifunctional mucinase in modulating personalized gut microbiota-Vibrio cholerae interactions during infection
双功能粘蛋白酶在感染期间调节个性化肠道微生物群-霍乱弧菌相互作用中的作用
- 批准号:
10749595 - 财政年份:2023
- 资助金额:
$ 78.45万 - 项目类别:
Vibrio cholerae antinitrosative stress defenses and gut microbiome interaction
霍乱弧菌抗亚硝化应激防御和肠道微生物组相互作用
- 批准号:
10681234 - 财政年份:2020
- 资助金额:
$ 78.45万 - 项目类别:
Vibrio cholerae antinitrosative stress defenses and gut microbiome interaction
霍乱弧菌抗亚硝化应激防御和肠道微生物组相互作用
- 批准号:
10269020 - 财政年份:2020
- 资助金额:
$ 78.45万 - 项目类别:
Gut microbiome-mediated small-molecule signaling and resistance to invading microorganisms
肠道微生物介导的小分子信号传导和对入侵微生物的抵抗力
- 批准号:
10218204 - 财政年份:2017
- 资助金额:
$ 78.45万 - 项目类别:
Gut microbiome-mediated small-molecule signaling and resistance to invading microorganisms
肠道微生物介导的小分子信号传导和对入侵微生物的抵抗力
- 批准号:
9753290 - 财政年份:2017
- 资助金额:
$ 78.45万 - 项目类别:
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