Stress-Mediated Regulation of HSV-1 Reactivation from Latency

项目摘要(&A) 单纯疱疹病毒1型(HSV-1)，一种重要的人类病原体，建立了终生 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。 外部应激源周期性地从潜伏期触发重新激活，导致复发 眼疾和脑炎。合成皮质类固醇地塞米松 显著增强潜伏感染HSV-1小鼠的潜伏期重新激活。 相反，糖皮质激素受体(GR)拮抗剂显著减少再激活 从延迟开始。由Wnt途径激活的转录因子b-catenin是 与应激诱导的再激活相比，潜伏期在更多的TG神经元中表达 提示b-连环蛋白可以维持潜伏期。GR和一种应激诱导转录因子， KRüppel样转录因子15(KLF15)，形成一个前馈环，协同作用 反式激活生产性感染所需的病毒即时早期启动子。基座 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，具有 对延迟-重新激活周期的多管齐下的影响。一个重要的早期步骤 重新激活是一种应激刺激，通过抑制典型的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KLF15合作 刺激病毒基因的表达，最终导致病毒的产生。在这方面的研究 提案将直接检验这一假设。对于目标1，HSV-1从延迟重新激活将 在TG或KLF15基因敲除小鼠中不表达GR的小鼠中与 野生型老鼠。对于目标2，我们将研究GR和KLF15如何协同 激活病毒转录。最后，差异表达的基因与 WNT/b-catenin信号通路将在潜伏期和重新激活期间确定 潜伏期(目标3)。这些研究的完成将揭示压力如何扰乱潜伏期和 直接刺激病毒基因的表达。 好了！

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 Based on these exciting unpublished studies, we hypothesize that stress, via GR activation, has multi-pronged effects on the latency-reactivation cycle.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. !