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:10357923
- 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 2024-02-29
- 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 infectionlong-term sequelaelytic 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)以潜伏感染的形式终生存在于周围神经元中。作为回应
由于神经元应激,病毒从潜伏期重新激活以允许再次感染。重新激活与
重大疾病。例如,重新激活后角膜中的复制会导致角膜炎。
重新激活后传播到中枢神经系统可导致单纯疱疹脑炎
(健康安全环境)。如果不进行治疗,HSE 的死亡率为 70%,即使经过治疗,许多幸存者仍表现出
长期后遗症。尽管有抗病毒药物可以限制 HSV 的有效复制,但尚无治疗方法
针对感染的潜伏阶段以防止其重新激活,并且没有针对 HSV 的疫苗。因此,我们的
长期目标是了解 HSV 如何应对神经元应激并制定预防策略
发生重新激活。我们的实验室和其他人已经证明病毒基因表达的机制
重新激活过程中的启动与病毒的从头感染不同。我们发现一个神经元
导致 c-Jun N 末端激酶 (JNK) 激活的应激途径会引发病毒染色质的变化
并允许重新激活。具体来说,与病毒启动子相关的组蛋白保持了修饰
与异染色质 (H3K9me3) 相关,但在 JNK 依赖性的 H3S10 上也被磷酸化
方式。使用我们开发的 HSV-1 潜伏期的初级神经元模型和小鼠模型
感染期间,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
被招募到病毒启动子中并识别参与 HSV-1 重新激活的其他细胞蛋白。我们将
还确定 JNK 信号传导如何克服 H3K27me3 抑制性组蛋白药物以允许
与此修饰相关的基因组的重新激活。最后,我们将研究其机制
ATRX 限制 HSV-1 重新激活并测试与 ATRX 相关的基因组非
允许重新激活。这些研究涉及潜伏病毒基因组和病毒基因组之间的密切相互作用。
神经元应激反应的启动尤其重要,因为它们提供了如何机制的见解
病毒会重新激活。因为病毒可能通过选择细胞途径来实现
重新激活,我们还将揭示对于宿主对神经元应激反应很重要的过程。
重要的是,通过了解 HSV 重新激活的最早事件,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(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Strength in diversity: Understanding the pathways to herpes simplex virus reactivation.
多样性的力量:了解单纯疱疹病毒重新激活的途径。
- DOI:10.1016/j.virol.2018.07.011
- 发表时间:2018-09
- 期刊:
- 影响因子:3.7
- 作者:Suzich JB;Cliffe AR
- 通讯作者:Cliffe AR
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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:
10112968 - 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:
8316708 - 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:
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:
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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:
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