VZV in the enteric nervous system: pathogenesis and consequences
VZV in the enteric nervous system: pathogenesis and consequences
批准号:
9175467
负责人:
MICHAEL D GERSHON
金额:
$37.15万
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:
2011-08-01 至 2021-02-28
关键词:
Abdominal PainAdultAffectAnimal ModelAnimalsAttenuatedAutonomic ganglionAxonBiopsyCD4 Positive T LymphocytesCaviaCell fusionCell membraneCellsChickenpoxChickenpox VaccineChildChildhoodCorticotropin-Releasing HormoneCountryCranial NervesCutaneousCytoplasmic VesiclesCytosolDataDetectionDiagnosisDiseaseDyesEndoscopic BiopsyEndoscopyEnteralEnteric Nervous SystemEpidermisEventExanthemaGangliaGene ExpressionGenesHerpes zoster diseaseHerpesvirus 1Herpesvirus Type 3HistologicHome environmentHumanHyperalgesiaImmigrantImmunocompromised HostImmunologic Deficiency SyndromesImmunosuppressionIn VitroIndividualInfectionInjectableInterferonsIntestinesLabelLatent VirusLatent virus infection phaseLeadLesionLifeLife Cycle StagesLipidsLymphocyteLyticLytic PhaseMethodsModelingMolecularMorbidity - disease rateNervous system structureNeuronsOropharyngealPainPathogenesisPathologicPathway interactionsPatientsPopulationPostherpetic neuralgiaPrimary InfectionProteinsPublic HealthReceptor Protein-Tyrosine KinasesResearchSalivaSalivarySignal TransductionSkinStressSuggestionSurrogate MarkersSyndromeT-LymphocyteTacrolimusTechniquesTestingTissuesTonsilTranscriptVaccinationVaccinesViral GenomeViremiaVirus DiseasesVisceralZoster Vaccineallodyniaanterograde transportdodecyldimethylamine oxideexosomeexperienceimmunosuppressedin vivointravenous injectionlatent infectionmortalitynanoparticlenovelpathogenreactivation from latencyresponsesecondary infectionspinal nerve posterior roottooltransmission processviral DNAvirtual
中文摘要
总结
水痘带状疱疹病毒(VZV)在背根(DRG)和脑神经(CNG)中建立潜伏期
神经节后,其传播的主要感染(水痘;水痘)。VZV可以从延迟重新激活,
引起局部的继发感染(带状疱疹)。然而,VZV延迟不限于
DRG/CNG;潜伏性VZV存在于肠神经系统(ENS)中,几乎每个人都有
经历水痘或接受水痘减毒活疫苗。VZV在ENS(肠道)中重新激活
带状疱疹),如在DRG/CNG中一样,但由于肠神经元缺乏皮肤投射,
没有皮疹,可能是胃肠道疾病的意外原因。VZV研究的一个主要障碍是
缺乏合适的动物模型。为了克服这个困难,我们证明了VZV感染,
建立潜伏期,并在分离的豚鼠肠神经元中重新激活;此外,VZV感染豚鼠
猪体内,在其DRG/CNG和ENS中建立潜伏感染,并且可以重新激活以产生
类似播散性带状疱疹的继发感染。VZV可以从感染者转移到ENS
DRG神经元轴突中的表皮投射到皮肤和肠道,但静脉注射VZV-
感染的T淋巴细胞在动物的几乎每个ENS和DRG神经元中建立潜伏期。已经
认为无细胞VZV(VZVCF)可以建立肠神经元的潜伏感染,而细胞VZVCF不能建立肠神经元的潜伏感染
相关VZV(VZVCA)。然而,VZV感染的淋巴细胞不分泌VZVCF,但它们能够
在体外和体内将感染传递到神经元,这是完全潜伏的。目标1检验以下假设:(i)
渐逝细胞融合负责VZV从淋巴细胞向神经元的传递;(ii)外泌体
来源于VZV感染的淋巴细胞,将干扰素基因刺激物(STING)引入神经元;(iii)
STING诱导神经元中的1型干扰素应答,其抑制VZV增殖并促进VZV增殖。
建立潜伏期。目的2检验以下假设:(i)VZV感染的淋巴细胞可诱导水痘-
如豚鼠的原发性感染,如果免疫抑制和应激先于感染;(ii)限制
VZV潜伏期允许局限于肠道或皮肤的局部再激活;(iii)持续激活的VZV潜伏期,
受体酪氨酸激酶转导途径,类似于HSV 1在交感神经元中的再激活,
调节肠神经元中潜伏的VZV基因组。目的3直接验证唾液VZV DNA
在不明原因腹痛严重到足以保证内镜检查和活检的患者中,
肠带状疱疹为了用组织诊断来验证这一想法,我们将分析唾液和胃肠道中的VZV DNA,
粘膜表达gE转录物和蛋白质,这将表明生产性VZV感染(肠
带状疱疹)。这项研究首次使用了一种新的动物模型,其中VZV在体内重新激活
以及首次应用非侵入性技术来识别可能患有肠道带状疱疹的患者。
英文摘要
Summary
Varicella zoster virus (VZV) famously establishes latency in dorsal root (DRG) and cranial nerve (CNG)
ganglia after its disseminated primary infection (varicella; chickenpox). VZV can reactivate from latency to
cause a localized secondary infection (zoster; shingles). VZV latency, however, is not restricted to
DRG/CNG; latent VZV is present in the enteric nervous system (ENS) in virtually everyone who has
experienced varicella or received the live attenuated varicella vaccine. VZV reactivates in the ENS (enteric
zoster) as it does in DRG/CNG but because enteric neurons lack cutaneous projections, enteric zoster occurs
without rash and may be an unsuspected cause of GI disease. A major hindrance to research on VZV has
been the absence of a suitable animal model. To overcome this difficulty, we demonstrated that VZV infects,
establishes latency, and reactivates in isolated guinea pig enteric neurons; moreover, VZV infects guinea
pigs in vivo, establishes latent infection in their DRG/CNG and ENS, and can be reactivated to produce a
secondary infection resembling disseminated zoster. VZV can be transported to the ENS from infected
epidermis in axons of DRG neurons that project both to the skin and gut but intravenous injection of VZV-
infected T lymphocytes establishes latency in almost every ENS and DRG neuron of the animal. It had been
thought that latent infection of enteric neurons could be established by cell-free VZV (VZVCF) but not by cell
associated VZV (VZVCA). VZV-infected lymphocytes, however, do not secrete VZVCF but they are able
transmit infection to neurons in vitro and in vivo that is exclusively latent. Aim 1 tests hypotheses that: (i)
evanescent cell fusion is responsible for transmission of VZV from lymphocytes to neurons; (ii) exosomes
derived from VZV-infected lymphocytes introduce stimulator of interferon genes (STING) to neurons; (iii)
STING induces a type1 interferon response in neurons that inhibits VZV proliferation and facilitates
establishment of latency. Aim 2 tests hypotheses that: (i) VZV-infected lymphocytes can induce a varicella-
like primary infection in guinea pigs if immunosuppression and stress precedes infection; (ii) restriction of
VZV latency allows localized reactivations to be confined to gut or skin; (iii) continuous activation of a
receptor tyrosine kinase transduction pathway, similar to that in HSV1 reactivation in sympathetic neurons,
regulates latent VZV genomes in enteric neurons. Aim 3 directly tests the hypothesis that salivary VZV DNA
in patients with unexplained abdominal pain severe enough to warrant endoscopy and biopsy is a marker of
enteric zoster. To validate this idea with a tissue diagnosis, we will analyze VZV DNA in saliva and GI
mucosal expression of gE transcripts and protein which would indicate productive VZV infection (enteric
zoster) in the bowel. This research makes the first use a novel animal model in which VZV reactivates in vivo
and the first application of a non-invasive technique to identify patients that might have enteric zoster.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
VZV in the enteric nervous system: pathogenesis and consequences
-
批准号:8516884
-
项目类别:
-
资助金额:$33.58万
-
财政年份:2011
-
负责人:MICHAEL D GERSHON
-
依托单位:
VZV in the enteric nervous system: pathogenesis and consequences
-
批准号:8704927
-
项目类别:
-
资助金额:$34.8万
-
财政年份:2011
-
负责人:MICHAEL D GERSHON
-
依托单位:
VZV in the enteric nervous system: pathogenesis and consequences
-
批准号:8308385
-
项目类别:
-
资助金额:$34.8万
-
财政年份:2011
-
负责人:MICHAEL D GERSHON
-
依托单位:
VZV in the enteric nervous system: pathogenesis and consequences
-
批准号:8153660
-
项目类别:
-
资助金额:$40.0万
-
财政年份:2011
-
负责人:MICHAEL D GERSHON
-
依托单位:
Development of the enteric nervous system: Cells & genes
-
批准号:7112563
-
项目类别:
-
资助金额:$1.8万
-
财政年份:2006
-
负责人:MICHAEL D GERSHON
-
依托单位:
PATHOBIOLOGY OF GI INFECTION AND INFLAMATION
-
批准号:6735677
-
项目类别:
-
资助金额:$17.58万
-
财政年份:2001
-
负责人:MICHAEL D GERSHON
-
依托单位:
PATHOBIOLOGY OF GI INFECTION AND INFLAMATION
-
批准号:6215943
-
项目类别:
-
资助金额:$7.72万
-
财政年份:2001
-
负责人:MICHAEL D GERSHON
-
依托单位:
PATHOBIOLOGY OF GI INFECTION AND INFLAMATION
-
批准号:7015532
-
项目类别:
-
资助金额:$4.13万
-
财政年份:2001
-
负责人:MICHAEL D GERSHON
-
依托单位:
PATHOBIOLOGY OF GI INFECTION AND INFLAMATION
-
批准号:6628379
-
项目类别:
-
资助金额:$17.23万
-
财政年份:2001
-
负责人:MICHAEL D GERSHON
-
依托单位:
PATHOBIOLOGY OF GI INFECTION AND INFLAMATION
-
批准号:6497863
-
项目类别:
-
资助金额:$12.34万
-
财政年份:2001
-
负责人:MICHAEL D GERSHON
-
依托单位:
PATHOBIOLOGY OF GI INFECTION AND INFLAMATION
-
批准号:6850772
-
项目类别:
-
资助金额:$17.58万
-
财政年份:2001
-
负责人:MICHAEL D GERSHON
-
依托单位:
CONFERENCE ON THE ENTERIC NERVOUS SYSTEM
-
批准号:2547055
-
项目类别:
-
资助金额:$1.5万
-
财政年份:1998
-
负责人:MICHAEL D GERSHON
-
依托单位:
FASEB SUMMER RESEARCH CONFERENCE: CELL/MOLECULAR BIOLOGY
-
批准号:3434689
-
项目类别:
-
资助金额:$1.0万
-
财政年份:1991
-
负责人:MICHAEL D GERSHON
-
依托单位:
SEROTONIN RECEPTORS: CHARACTERIZATION & ONTOGENY
-
批准号:3405320
-
项目类别:
-
资助金额:$15.18万
-
财政年份:1986
-
负责人:MICHAEL D GERSHON
-
依托单位:
SEROTONIN RECEPTORS--CHARACTERIZATION & ONTOGENY
-
批准号:3405321
-
项目类别:
-
资助金额:$15.86万
-
财政年份:1986
-
负责人:MICHAEL D GERSHON
-
依托单位:
SEROTONIN RECEPTORS: CHARACTERIZATION & ONTOGENY
-
批准号:2264577
-
项目类别:
-
资助金额:$15.82万
-
财政年份:1986
-
负责人:MICHAEL D GERSHON
-
依托单位:
SIMPLE VERTEBRATE AND INVERTEBRATE SYSTEMS
-
批准号:2379518
-
项目类别:
-
资助金额:$24.75万
-
财政年份:1984
-
负责人:MICHAEL D GERSHON
-
依托单位:
SIMPLE VERTEBRATE & INVERTEBRATE SYSTEMS
-
批准号:3543518
-
项目类别:
-
资助金额:$13.25万
-
财政年份:1984
-
负责人:MICHAEL D GERSHON
-
依托单位:
NEUROBIOLOGY
-
批准号:3543520
-
项目类别:
-
资助金额:$13.93万
-
财政年份:1984
-
负责人:MICHAEL D GERSHON
-
依托单位:
NEUROBIOLOGY
-
批准号:3543514
-
项目类别:
-
资助金额:$15.57万
-
财政年份:1984
-
负责人:MICHAEL D GERSHON
-
依托单位:
海外基金