Ostler Jeffery B, Jones Clinton
Department of Veterinary Pathobiology, Oklahoma State University, College of Veterinary Medicine, Stillwater, Oklahoma, USA.
J Virol. 2025 Aug 19;99(8):e0074725. doi: 10.1128/jvi.00747-25. Epub 2025 Jul 22.
Bovine alphaherpesvirus 1 (BoHV-1) continues to be a significant bovine pathogen. Acute infections culminate in lifelong latent infections in sensory neurons of trigeminal ganglia (TG) and the central nervous system. The synthetic corticosteroid dexamethasone consistently initiates BoHV-1 reactivation from latency in calves or rabbits. The immediate early transcription unit 1 (IEtu1) promoter contains two glucocorticoid receptor (GR) response elements and drives the expression of infected cell protein 0 (bICP0) and bICP4. GR, Krüppel-like Factor 15 (KLF15), and dexamethasone treatment cooperatively transactivate the IEtu1 promoter. Conversely, the bICP0 early (E) promoter is cooperatively transactivated by two pioneer transcription factors, GR and KLF4, that are capable of binding silent heterochromatin and activating transcription. Consequently, we hypothesized that GR activates IEtu1 and bICP0 E promoters, which trigger productive infection and reactivation from latency. Notably, BoHV-1 does not replicate in GR null monkey kidney cells (COS-7), unless a GR expression plasmid is transfected with the BoHV-1 genome. Furthermore, GR occupancy of IEtu1 and bICP0 E promoters correlates with viral replication in COS-7 cells. In TG of latently infected calves, IEtu1 and bICP0 E promoters were occupied by a heterochromatin marker H3K9me3 (histone 3 trimethylation at lysine 9), but not GR. Following dexamethasone treatment of latently infected calves for 3 hours, IEtu1 and bICP0 E promoters were occupied by GR and histone 3 acetylated at lysine 9, which correlates with active transcription. Collectively, these studies provide new insights into the mechanism by which stress triggers bICP0 and bICP4 protein expression during reactivation from latency.
Bovine alphaherpesvirus 1 (BoHV-1), a significant pathogen, establishes life-long latency in certain neurons. Dexamethasone, a synthetic corticosteroid, consistently induces BoHV-1 reactivation from latency. Glucocorticoid receptor (GR) and dexamethasone transactivate the immediate early transcription unit 1 (IEtu1) promoter, which drives expression of infected cell protein 0 (bICP0) and bICP4. GR also transactivates the bICP0 early (E) promoter via a ligand-independent manner. Notably, GR and DEX induced BoHV-1 replication in non-permissive COS-7 cells. Furthermore, GR and a histone 3 marker, H3K9 acetylation, are associated with active chromatin and occupy the IEtu1 and bICP0 E promoters when latently infected calves are treated with dexamethasone for 3 hours. Conversely, a heterochromatin marker, histone 3 trimethylated at lysine 9, but not GR, occupied these viral promoters during latency. These studies revealed that GR and dexamethasone play crucial roles in chromatin remodeling of IEtu1 and bICP0 E promoters, which correlate with viral replication and reactivation from latency.
牛α疱疹病毒1型（BoHV-1）仍然是一种重要的牛病原体。急性感染最终会在三叉神经节（TG）的感觉神经元和中枢神经系统中形成终身潜伏感染。合成皮质类固醇地塞米松始终能引发BoHV-1从潜伏状态重新激活，在犊牛或兔子中均是如此。立即早期转录单元1（IEtu1）启动子包含两个糖皮质激素受体（GR）反应元件，并驱动感染细胞蛋白0（bICP0）和bICP4的表达。GR、类 Kruppel 样因子15（KLF15）和地塞米松处理协同反式激活IEtu1启动子。相反，bICP0早期（E）启动子由两个先锋转录因子GR和KLF4协同反式激活，这两个因子能够结合沉默异染色质并激活转录。因此，我们推测GR激活IEtu1和bICP0 E启动子，从而引发潜伏感染的激活和生产性感染。值得注意的是，BoHV-1在GR基因敲除的猴肾细胞（COS-7）中不复制，除非将GR表达质粒与BoHV-1基因组一起转染。此外，GR对IEtu1和bICP0 E启动子的占据与COS-7细胞中的病毒复制相关。在潜伏感染犊牛的TG中，IEtu1和bICP0 E启动子被异染色质标记H3K9me3（赖氨酸9处的组蛋白3三甲基化）占据，但未被GR占据。在用潜伏感染的犊牛进行3小时地塞米松处理后，IEtu1和bICP0 E启动子被GR和赖氨酸9处乙酰化的组蛋白3占据，这与活跃转录相关。总的来说，这些研究为应激在潜伏激活过程中触发bICP0和bICP4蛋白表达的机制提供了新的见解。
牛α疱疹病毒1型（BoHV-1）是一种重要病原体，在某些神经元中建立终身潜伏感染。合成皮质类固醇地塞米松始终能诱导BoHV-1从潜伏状态重新激活。糖皮质激素受体（GR）和地塞米松反式激活立即早期转录单元1（IEtu1）启动子，该启动子驱动感染细胞蛋白0（bICP0）和bICP4的表达。GR还通过不依赖配体的方式反式激活bICP0早期（E）启动子。值得注意的是，GR和地塞米松诱导BoHV-1在非允许性COS-7细胞中复制。此外，当用潜伏感染的犊牛进行3小时地塞米松处理时，GR和组蛋白3标记H3K9乙酰化与活跃染色质相关，并占据IEtu1和bICP0 E启动子。相反，在潜伏期间，异染色质标记赖氨酸9处三甲基化的组蛋白3而非GR占据这些病毒启动子。这些研究表明，GR和地塞米松在IEtu1和bICP0 E启动子的染色质重塑中起关键作用，这与病毒复制和潜伏激活相关。
