Characterization of a commensal enteric virus
Characterization of a commensal enteric virus
批准号:
10458130
负责人:
Ken Hashigiwa Cadwell
金额:
$54.8万
依托单位国家:
美国
项目类别:
财政年份:
2011
资助国家:
美国
项目状态:
已结题
起止时间:
2011-09-20 至 2023-08-31
关键词:
AddressAdolescentAnimal ModelAnimalsAnti-Inflammatory AgentsAttentionAutophagocytosisAwardBacteriaBacterial InfectionsBiological ModelsCell DeathCell SurvivalCellsCessation of lifeChemical InjuryChildhoodChronic DiseaseCitrobacter rodentiumCrohn&aposs diseaseDataDefectDegradation PathwayDetectionDevelopmentDiarrheaDiseaseEnteralEpithelialEpithelial CellsEventFundingGastrointestinal DiseasesGastrointestinal tract structureGerm-FreeGram-Negative Bacterial InfectionsHealthHost DefenseHumanImmune System DiseasesImmune responseImmune systemInfectionInflammatoryInflammatory Bowel DiseasesInjuryInterferonsInterventionIntestinesKnock-outKnowledgeLicensingLifeLymphocyteMass Spectrum AnalysisMediatingMicrobeModelingMolecularMusMutant Strains MiceMutationNatureNecrosisNorovirusOpportunistic InfectionsOrganismOrganoidsPaneth CellsPathogenesisPathway interactionsPhysiologicalPhysiologyPopulationPredispositionProcessProductionRNAReporterResolutionRoleSeriesSignal TransductionSusceptibility GeneSystemT-LymphocyteTechniquesTestingTimeTissuesViralVirusWeaningadverse outcomeantimicrobialcell typecross immunitycytotoxicenteric infectionexperimental studyfecal transplantationgut colonizationgut microbiotaimprovedin vitro Modelin vivoindividual patientinnovationinsightinterleukin-22membermicrobiotamitochondrial autophagymortalitymouse geneticsnovelpathogenpathogenic bacteriaprebioticspreventprogramsresilienceresponsesensorstem cell nichesymbionttissue injury
中文摘要
项目摘要
越来越多的证据支持肠道微生物群的细菌成员在宿主防御中的作用,
免疫紊乱,如炎症性肠病(IBD)。哺乳动物的胃肠道也
藏匿着多种动物病毒尽管它们无处不在,
肠道定植的病毒超出其作为肠道病原体的作用还不清楚。比上一
在该奖项的资助期间,我们开发了鼠诺如病毒(MNV)模型作为一种易于处理的实验
这是我们知识中的一个重大空白。我们发现MNV可以作为一种共生病毒,
为宿主提供益处,例如防止继发性细菌感染。与此同时,MNV
诱导Atg16L1突变的小鼠肠道异常,Atg16L1是一种IBD易感基因,
在自噬的细胞降解途径中。本提案的主要目的是使用MNV模型
确定肠道定植是否由病毒共生体导致有益的
或对宿主产生不利影响。我们介绍的数据表明,MNV感染可以显着改善
革兰氏阴性细菌病原体柠檬酸杆菌致死感染后新断奶小鼠的存活率
啮齿动物。我们建议使用这个模型来阐明RNA传感途径是如何被病毒诱导的,
共生体介导的交叉保护在生命早期感染的肠道细菌病原体,一个主要原因
死亡率。与此同时,我们将研究Atg16L1突变如何使原本有益的病毒变得
有害我们的初步数据提示了一种新的机制,即MNV感染取代了抗炎作用。
肠道中的淋巴细胞具有细胞毒性亚群,可诱导潘氏细胞坏死死亡,潘氏细胞是一种关键的分泌上皮细胞,
与人类IBD有关的细胞。定义这些过程的机械细节将产生新的见解,
肠道中病毒共生体的性质,并可能揭示新的途径参与组织损伤的解决,
与先前在细菌定殖期间检查的那些不同。
英文摘要
PROJECT SUMMARY
Accumulating evidence support the role of bacterial members of the gut microbiota in host defense and a variety
of immune disorders, such as inflammatory bowel disease (IBD). The mammalian gastrointestinal tract also
harbors diverse animal viruses. Despite their ubiquitous presence, the functional and mechanistic consequences
of intestinal colonization by viruses beyond their role as diarrheal pathogens has been unclear. Over the previous
funding periods of this award, we developed the murine norovirus (MNV) model as a tractable experimental
system to address this major gap in our knowledge. We found that MNV can function as a symbiotic virus by
providing benefits to the host, such as protection against secondary bacterial infection. At the same time, MNV
induces intestinal abnormalities in mice with a mutation in Atg16L1, an IBD susceptibility gene that participates
in the cellular degradative pathway of autophagy. The main objective of this proposal is to use the MNV model
to define the mechanisms that determine whether intestinal colonization by a viral symbiont leads to beneficial
or adverse outcomes for the host. We introduce data showing that MNV infection can significantly improve
survival of newly weaned mice from lethal infection by the Gram-negative bacterial pathogen Citrobacter
rodentium. We propose to use this model to elucidate how RNA sensing pathways are induced by a viral
symbiont to mediate cross-protection during early-life infection by an enteric bacterial pathogen, a leading cause
of mortality. In parallel, we will investigate how Atg16L1 mutation makes an otherwise beneficial virus become
harmful. Our preliminary data suggests a novel mechanism in which MNV infection replaces anti-inflammatory
lymphocytes in the gut with cytotoxic subsets that induce necrotic death of Paneth cells, a key secretory epithelial
cell implicated in human IBD. Defining the mechanistic details of these processes will yield new insight into the
nature of a viral symbiont in the gut, and may reveal new pathways involved in the resolution of tissue injury that
are distinct from those previously examined during bacterial colonization.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Mechanisms of MRSA intestinal colonization
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批准号:10321574
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项目类别:
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资助金额:$69.97万
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财政年份:2020
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负责人:Ken Hashigiwa Cadwell
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依托单位:
Mechanisms of MRSA intestinal colonization
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批准号:9903060
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财政年份:2020
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依托单位:
Interactions between helminth colonization and the gut microbiota
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批准号:10318081
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项目类别:
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资助金额:$66.03万
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财政年份:2018
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负责人:Ken Hashigiwa Cadwell
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依托单位:
Redefining the role of autophagy in bacterial disease
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批准号:10519116
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项目类别:
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资助金额:$6.26万
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财政年份:2016
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依托单位:
Redefining the role of autophagy in bacterial disease
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批准号:10053295
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项目类别:
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资助金额:$51.51万
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财政年份:2016
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负责人:Ken Hashigiwa Cadwell
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依托单位:
Redefining the role of autophagy in bacterial disease
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批准号:10764559
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项目类别:
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资助金额:$55.11万
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财政年份:2016
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负责人:Ken Hashigiwa Cadwell
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依托单位:
Redefining the role of autophagy in bacterial disease
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批准号:10384537
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项目类别:
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资助金额:$61.65万
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财政年份:2016
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负责人:Ken Hashigiwa Cadwell
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依托单位:
The role of autophagy gene Atg16L1 in allogeneic hematopoietic stem cell transplantation - Renewal - 1
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批准号:9915940
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项目类别:
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资助金额:$71.93万
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财政年份:2015
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负责人:Ken Hashigiwa Cadwell
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依托单位:
The role of autophagy gene Atg16L1 in allogeneic hematopoietic stem cell transplantation - Renewal - 1
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批准号:9763726
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项目类别:
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资助金额:$73.66万
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财政年份:2015
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负责人:Ken Hashigiwa Cadwell
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依托单位:
The role of autophagy gene Atg16L1 in allogeneic hematopoietic stem cell transplantation - Renewal - 1
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批准号:10410421
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项目类别:
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资助金额:$71.93万
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财政年份:2015
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负责人:Ken Hashigiwa Cadwell
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依托单位:
Role of Nod2 in preventing intestinal disease downstream of microbial imbalances
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批准号:9105377
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项目类别:
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资助金额:$42.38万
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财政年份:2015
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负责人:Ken Hashigiwa Cadwell
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依托单位:
The role of autophagy gene Atg16L1 in allogeneic hematopoietic stem cell transplantation - Renewal - 1
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批准号:10165785
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项目类别:
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资助金额:$71.93万
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财政年份:2015
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负责人:Ken Hashigiwa Cadwell
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依托单位:
The role of autophagy gene Atg16L1 in allogeneic hematopoietic stem cell transplantation - Resubmission - 1
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批准号:9128035
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项目类别:
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资助金额:$55.06万
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财政年份:2015
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负责人:Ken Hashigiwa Cadwell
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依托单位:
Role of Nod2 in preventing intestinal disease downstream of microbial imbalances
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批准号:8961237
-
项目类别:
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资助金额:$42.38万
-
财政年份:2015
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负责人:Ken Hashigiwa Cadwell
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依托单位:
Defining the role of Nod2 and bacteria in Atg16L1-dependent intestinal disease.
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批准号:8785508
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项目类别:
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资助金额:$8.85万
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财政年份:2014
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负责人:Ken Hashigiwa Cadwell
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依托单位:
Characterization of a commensal enteric virus
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批准号:9298638
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项目类别:
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资助金额:$44.93万
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财政年份:2011
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负责人:Ken Hashigiwa Cadwell
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依托单位:
Diabetes, Digestive, and Kidney Diseases Extramural Research
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批准号:10859511
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项目类别:
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资助金额:$52.54万
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财政年份:2011
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负责人:Ken Hashigiwa Cadwell
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依托单位:
Characterization of a commensal enteric virus
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批准号:10266190
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项目类别:
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资助金额:$55.47万
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财政年份:2011
-
负责人:Ken Hashigiwa Cadwell
-
依托单位:
Defining the role of Nod2 and bacteria in Atg16L1-dependent intestinal disease.
-
批准号:8616856
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项目类别:
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资助金额:$2.22万
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财政年份:2011
-
负责人:Ken Hashigiwa Cadwell
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依托单位:
Defining the role of Nod2 and bacteria in Atg16L1-dependent intestinal disease.
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批准号:8515405
-
项目类别:
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资助金额:$40.61万
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财政年份:2011
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负责人:Ken Hashigiwa Cadwell
-
依托单位:
海外基金