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：
Anna Ruth Cliffe
金额：
$ 35.02万
依托单位：
UNIVERSITY OF VIRGINIA
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：
https://reporter.nih.gov/project-details/10357923
关键词：
ATRX gene Antiviral Agents Binding Proteins Cellular Stress ChIP-seq Chromatin Chromatin Structure Complex Cornea DNA DNA Binding DNA Sequence Data Disease Encephalitis Epigenetic Process Event Excision Exhibits Fatality rate Gene Expression Genital Genitalia Genome Goals Herpes encephalitis Herpesvirus 1 Heterochromatin Heterogeneity Histone H3 Histones Immune response Immunofluorescence Immunologic Infection Inflammation JUN gene Keratitis Lesion Life Light Link Lysine Lytic MAPK8 gene Mediating Mediator of activation protein Modeling Modification Molecular Morbidity - disease rate N-terminal Neuraxis Neurons Oral cavity Pathway interactions Peptides Peripheral Pharmaceutical Preparations Phosphorylation Phosphotransferases Process Proteins Recurrence Role Serine Signal Transduction Simplexvirus Site Stress Survivors System Testing Transcriptional Activation Up-Regulation Vaccines Viral Viral Gene Expression Regulation Viral Genes Viral Genome Virus Virus Activation Virus Latency biological adaptation to stress demethylation gene induction histone demethylase in vitro Model in vivo Model insight knock-down latent infection long-term sequelae lytic gene expression mortality mouse model novel prevent promoter reactivation from latency recruit response small hairpin RNA targeted treatment therapy development transmission 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.

项目摘要/摘要单纯疱疹病毒（HSV）以潜在感染的形式在周围神经元中持续生命。作为回应为了神经元胁迫，病毒从潜伏期重新激活以允许再感染。重新激活与重大疾病。例如，重新激活后角膜中的复制导致角膜炎。重新激活后向中枢神经系统传播会导致单纯疱疹脑炎（HSE）。没有治疗，HSE的死亡率为70％，即使经过治疗，许多幸存者也表现出来长期后遗症。尽管有抗病毒药物可限制HSV生产性复制，但没有疗法靶向潜在感染阶段以防止重新激活，并且没有针对HSV的疫苗。因此，我们的长期目标是了解HSV如何应对神经元压力并制定策略以防止重新激活发生。我们的实验室和其他实验室表明，病毒基因表达的机制在重新激活过程中的启动与病毒的从头感染不同。我们发现神经元应力途径导致C-Jun N末端激酶（JNK）激活触发病毒染色质的变化并允许重新激活。具体而言，与病毒启动子相关的组蛋白保持了修饰与异染色质（H3K9me3）相关方式。使用我们已经开发的HSV-1潜伏期的主要神经元模型和鼠标模型感染我们将确定JNK的激活如何允许在期间诱导病毒基因表达重新激活。通过执行候选蛋白的CHIP-SEQ和SHRNA敲低shrna，我们将研究JNK 被招募到病毒启动子并鉴定出参与HSV-1重新激活的其他细胞蛋白。我们将还可以确定JNK信号如何克服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，我们将研究以下机制 ATRX限制了HSV-1重新激活，并检验了与ATRX相关的基因组的假设允许重新激活。这些研究对潜在病毒基因组与神经元应力反应的启动特别重要，因为它们提供了机械洞察力的洞察力病毒经过重新激活。因为该病毒可能已经采用了实现的细胞途径重新激活，我们还将发现对宿主对神经元应力反应很重要的过程。重要的是，通过了解HSV重新激活中最早的事件，我们的长期目标是发展靶向潜在基因组并使其对重新激活无反应的疗法。