Cell stress-mediated changes in the Herpes simplex virus type 1 chromatin structure during reactivation from latent infection
单纯疱疹病毒1型染色质结构在潜伏感染重新激活过程中细胞应激介导的变化
基本信息
- 批准号:10112968
- 负责人:
- 金额:$ 35.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-03-15 至 2023-02-28
- 项目状态:已结题
- 来源:
- 关键词:ATRX geneAntiviral AgentsBinding ProteinsCellular StressChIP-seqChromatinChromatin StructureComplexCorneaDNADNA BindingDNA SequenceDataDiseaseEncephalitisEpigenetic ProcessEventExcisionExhibitsFatality rateGene ExpressionGenitalGenitaliaGenomeGoalsHerpes encephalitisHerpesvirus 1HeterochromatinHeterogeneityHistone H3HistonesImmune responseImmunofluorescence ImmunologicInfectionInflammationJUN geneKeratitisLesionLifeLightLinkLysineLyticMAPK8 geneMediatingMediator of activation proteinModelingModificationMolecularMorbidity - disease rateN-terminalNeuraxisNeuronsOral cavityPathway interactionsPeptidesPeripheralPharmaceutical PreparationsPhosphorylationPhosphotransferasesProcessProteinsRecurrenceRoleSerineSignal TransductionSimplexvirusSiteStressSurvivorsSystemTestingTranscriptional ActivationUp-RegulationVaccinesViralViral Gene Expression RegulationViral GenesViral GenomeVirusVirus ActivationVirus Latencybiological adaptation to stressdemethylationgene inductionhistone demethylasein vitro Modelin vivo Modelinsightknock-downlatent infectionlytic gene expressionmortalitymouse modelnovelpreventpromoterreactivation from latencyrecruitresponsesmall hairpin RNAtargeted treatmenttherapy developmenttransmission process
项目摘要
Project Summary/abstract
Herpes simplex virus (HSV) persists for life in peripheral neurons in the form of a latent infection. In response
to neuronal stress, the virus reactivates from latency to permit reinfection. Reactivation is associated with
significant disease. For example, replication in the cornea following reactivation results in keratitis.
Transmission to the central nervous system following reactivation can result in herpes simplex encephalitis
(HSE). Without treatment, HSE has a fatality rate of 70%, and even with treatment, many survivors exhibit
long-term sequelae. Although anti-viral drugs are available that limit HSV productive replication, no therapies
target the latent stage of infection to prevent reactivation and there is no vaccine against HSV. Therefore, our
long-term goals are to understand how HSV responds to neuronal stress and develop strategies to prevent
reactivation occurring. Our lab and others have shown that the mechanism by which viral gene expression
initiates during reactivation is distinct from de novo infection with the virus. We have found that a neuronal
stress pathway resulting in activation of c-Jun N-terminal kinase (JNK) triggers changes to the viral chromatin
and permits reactivation. Specifically, the histones associated with viral promoters maintained a modification
associated with heterochromatin (H3K9me3) but also became phosphorylated on H3S10 in a JNK-dependent
manner. Using both a primary neuronal model of HSV-1 latency that we have developed and mouse models of
infection we will determine how activation of JNK permits viral gene expression to be induced during
reactivation. By performing ChIP-seq and shRNA knock-down of candidate proteins, we will examine how JNK
gets recruited to viral promoters and identify additional cellular proteins involved in HSV-1 reactivation. We will
also determine how JNK signaling overcomes the H3K27me3 repressive histone medication to permit
reactivation from genomes associated with this modification. Finally, we will examine the mechanism that
ATRX restricts HSV-1 reactivation and test the hypothesis that genomes associated with ATRX are non-
permissive for reactivation. These studies into the intimate interaction between the latent viral genome and
initiation of a neuronal stress response are especially significant as they provide mechanistic insight into how
the virus undergoes reactivation. Because the virus has likely co-opted cellular pathway to achieve
reactivation, we will also uncover process that are important for the host response to neuronal stress.
Importantly, by understanding the very earliest events in HSV reactivation, our long-term goals are to develop
therapies that target the latent genome and make it unresponsive for reactivation.
项目概要/摘要
单纯疱疹病毒(HSV)以潜伏感染的形式在外周神经元中持续存在。响应
神经元应激时,病毒从潜伏期重新激活,允许再次感染。重新激活与
重大疾病。例如,再活化后角膜中的复制导致角膜炎。
传播到中枢神经系统后重新激活可导致单纯疱疹病毒性脑炎
(HSE)。如果不治疗,HSE的死亡率为70%,即使接受治疗,许多幸存者也表现出
长期后遗症虽然抗病毒药物可限制HSV的生产性复制,但没有治疗方法。
针对感染的潜伏阶段,以防止重新激活,并且没有针对HSV的疫苗。所以我们的
长期目标是了解HSV如何对神经元应激做出反应,并制定预防策略。
重新激活发生。我们的实验室和其他实验室已经证明了病毒基因表达的机制
在再活化期间启动的病毒不同于病毒的从头感染。我们发现一个神经元
导致c-Jun N-末端激酶(JNK)活化的应激途径触发病毒染色质的变化
并允许再活化。具体来说,与病毒启动子相关的组蛋白保持了一种修饰,
与异染色质(H3 K9 me 3)相关,但也在JNK依赖性磷酸化中在H3 S10上磷酸化。
方式使用我们已经开发的HSV-1潜伏期的初级神经元模型和HSV-1潜伏期的小鼠模型,
我们将确定JNK的激活如何允许病毒基因表达被诱导,
重新激活通过对候选蛋白进行ChIP-seq和shRNA敲低,我们将研究JNK如何在细胞内表达。
被招募到病毒启动子中,并鉴定出参与HSV-1再激活的其他细胞蛋白。我们将
还确定JNK信号传导如何克服H3 K27 me 3抑制性组蛋白药物,
从与这种修饰相关的基因组中重新激活。最后,我们将研究
ATRX限制HSV-1的再激活,并检验与ATRX相关的基因组是非特异性的假设。
允许重新激活。这些关于潜伏病毒基因组与病毒之间的密切相互作用的研究,
神经元应激反应起始是特别重要的,因为它们提供了关于如何
病毒会被重新激活因为病毒很可能通过细胞途径
我们还将揭示宿主对神经元应激反应的重要过程。
重要的是,通过了解HSV再激活的最早期事件,我们的长期目标是开发
针对潜在基因组并使其对重新激活无反应的疗法。
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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Anna Ruth Cliffe其他文献
Anna Ruth Cliffe的其他文献
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{{ truncateString('Anna Ruth Cliffe', 18)}}的其他基金
Investigating the role of long-term latent herpes simplex virus infection on APOE4-associated Alzheimer's disease pathogenesis
研究长期潜伏的单纯疱疹病毒感染对 APOE4 相关阿尔茨海默病发病机制的作用
- 批准号:
10740641 - 财政年份:2023
- 资助金额:
$ 35.02万 - 项目类别:
Cell stress-mediated changes in the Herpes simplex virus type 1 chromatin structure during reactivation from latent infection
单纯疱疹病毒1型染色质结构在潜伏感染重新激活过程中细胞应激介导的变化
- 批准号:
10357923 - 财政年份:2018
- 资助金额:
$ 35.02万 - 项目类别:
Intersection of HSV latency and reactivation with the neuronal apoptotic pathway
HSV 潜伏期和再激活与神经元凋亡途径的交叉点
- 批准号:
8432969 - 财政年份:2012
- 资助金额:
$ 35.02万 - 项目类别:
Intersection of HSV latency and reactivation with the neuronal apoptotic pathway
HSV 潜伏期和再激活与神经元凋亡途径的交叉点
- 批准号:
8628197 - 财政年份:2012
- 资助金额:
$ 35.02万 - 项目类别:
Intersection of HSV latency and reactivation with the neuronal apoptotic pathway
HSV 潜伏期和再激活与神经元凋亡途径的交叉点
- 批准号:
8316708 - 财政年份:2012
- 资助金额:
$ 35.02万 - 项目类别:
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