Stress-Mediated Regulation of HSV-1 Reactivation from Latency

应激介导的 HSV-1 潜伏期再激活调节

• 批准号: 10133169
• 负责人: CLINTON J JONES
• 金额: $ 35.16万
• 依托单位: OKLAHOMA STATE UNIVERSITY STILLWATER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10133169
• 关键词: Address; Adrenal Cortex Hormones; Alzheimer' s Disease; Axon; Binding; Brain Stem; ChIP-seq; Chronic stress; Complex; Dexamethasone; Disease; Early Promoters; Encephalitis; Eye Infections; Eye diseases; Frequencies; Gene Expression; Genes; Genetic Transcription; Genomics; Glucocorticoid Receptor; Health; Herpesvirus 1; Human; Immune; Incidence; Incubated; Infection; Knockout Mice; Kruppel-like transcription factors; Lead; Life; Lytic Phase; Maintenance; Mediating; Metabolic; Microarray Analysis; Modeling; Molecular; Mucous Membrane; Mus; Mutant Strains Mice; Neurons; Pathway interactions; Physiological; Production; Promoter Regions; Proteins; Publishing; Receptor Activation; Recurrence; Recurrent disease; Regulation; Research Design; Signal Pathway; Stimulus; Stress; Structure of trigeminal ganglion; Surface; Testing; VP 16; Viral; Viral Genes; Viral Regulatory Proteins; Virus; Virus Shedding; Wild Type Mouse; acute infection; acute stress; base; beta catenin; differential expression; glucocorticoid receptor alpha; human pathogen; innovation; insight; latency associated transcript; latent infection; mutant; neuronal survival; promoter; protein activation; protein expression; psychologic; reactivation from latency; repaired; stressor; transcription factor; viral transmission

Project Summary & Abstract Herpes simplex virus 1 (HSV-1), an important human pathogen, establishes life-long latency in neurons within trigeminal ganglia (TG) and CNS, including brainstem. External stressors periodically trigger reactivation from latency, resulting in recurrent ocular disease and encephalitis. The synthetic corticosteroid dexamethasone significantly enhances reactivation from latency in HSV-1 latently infected mice. Conversely, a glucocorticoid receptor (GR) antagonist significantly reduces reactivation from latency. A transcription factor activated by the Wnt pathway, b-catenin, is expressed in more TG neurons during latency relative to stress induced reactivation suggesting b-catenin maintains latency. GR and a stress induced transcription factor, Krüppel like transcription factor 15 (KLF15), form a feed forward loop that synergistically transactivates viral immediate early promoters required for productive infection. Based on these exciting unpublished studies, we hypothesize that stress, via GR activation, has multi-pronged effects on the latency-reactivation cycle. An important early step during reactivation is a stressful stimulus disrupts latency by suppressing the canonical Wnt/b- catenin signaling pathway. A second early step is GR and KLF15 cooperatively stimulate viral gene expression, ultimately leading to virus production. Studies in this proposal will directly test this hypothesis. For Aim 1, HSV-1 reactivation from latency will be compared in mice that do not express GR in TG or KLF15 knockout mice relative to wild-type mice. For Aim 2, we will investigate how GR and KLF15 synergistically activate viral transcription. Finally, differentially expressed genes associated with the Wnt/b-catenin signaling pathway will be identified during latency and reactivation from latency (Aim 3). Completion of these studies will reveal how stress disrupts latency and directly stimulates viral gene expression. !

项目概要和摘要 单纯疱疹病毒1（HSV-1）是一种重要的人类病原体， 三叉神经节（TG）和CNS（包括脑干）内神经元的潜伏期。 外部压力周期性地触发潜伏期的再激活，导致复发性 眼病和脑炎。合成皮质类固醇地塞米松 显著增强HSV-1潜伏感染小鼠中潜伏期的再激活。 相反，糖皮质激素受体（GR）拮抗剂显著降低再激活 从latency。由Wnt途径激活的转录因子，b-连环蛋白， 相对于应激诱导的再激活，在潜伏期期间在更多的TG神经元中表达 表明β-连环蛋白维持潜伏期。GR和应激诱导转录因子， Krüppel样转录因子15（KLF 15），形成一个前馈环， 反式激活生产性感染所需的病毒立即早期启动子。基于 在这些令人兴奋的未发表的研究中，我们假设压力通过GR激活， 对潜伏-再激活周期的多重影响。这是一个重要的早期步骤， 重新激活是一种应激刺激，通过抑制经典Wnt/B-来扰乱潜伏期 连环蛋白信号通路。第二个早期步骤是GR和KLF 15合作 刺激病毒基因表达，最终导致病毒产生。研究的 该提案将直接检验这一假设。对于目标1，HSV-1从潜伏期的再激活将 在TG或KLF 15敲除小鼠中不表达GR的小鼠中， 野生型小鼠。对于目标2，我们将研究GR和KLF 15如何协同作用， 激活病毒转录。最后，差异表达的基因与 Wnt/β-连环蛋白信号通路将在潜伏期和再激活过程中被识别， 延迟（目标3）。这些研究的完成将揭示压力如何破坏潜伏期， 直接刺激病毒基因表达。 !