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: 10331857
• 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/10331857
• 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; antagonist; 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. !

项目总结及摘要 单纯疱疹病毒 1 (HSV-1) 是一种重要的人类病原体，可导致终生感染。 三叉神经节（TG）和中枢神经系统（包括脑干）内神经元的潜伏期。 外部压力源会定期触发潜伏期的重新激活，从而导致复发 眼部疾病和脑炎。合成皮质类固醇地塞米松 显着增强 HSV-1 潜伏感染小鼠的潜伏期再激活。 相反，糖皮质激素受体 (GR) 拮抗剂可显着减少再激活 来自延迟。由 Wnt 通路激活的转录因子 b-catenin 是 相对于应激诱导的再激活，潜伏期在更多 TG 神经元中表达 表明 β-连环蛋白保持潜伏期。 GR 和应激诱导转录因子， Krüppel 与转录因子 15 (KLF15) 类似，形成前馈环，协同作用 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， 对潜伏期-重新激活周期的多管齐下的影响。期间重要的早期步骤 重新激活是一种压力刺激，通过抑制典型的 Wnt/b- 来破坏潜伏期 连环蛋白信号通路。第二个早期步骤是 GR 和 KLF15 合作 刺激病毒基因表达，最终导致病毒产生。这方面的研究 提案将直接检验这个假设。对于目标 1，HSV-1 从潜伏期重新激活将 与 TG 或 KLF15 敲除小鼠中不表达 GR 的小鼠进行比较 野生型小鼠。对于目标 2，我们将研究 GR 和 KLF15 如何协同作用 激活病毒转录。最后，差异表达基因与 Wnt/b-连环蛋白信号通路将在潜伏期和重新激活期间被识别 延迟（目标 3）。完成这些研究将揭示压力如何破坏潜伏期和 直接刺激病毒基因表达。 ！