Lian Zhengmin, Zhao Yuan, Wen Wei, Zhu Zhenbang, Wang Wenqiang, Zhang Zhendong, Liu Panrao, Favoreel Herman W, Li Xiangdong
Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, China.
Department of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
J Virol. 2025 Feb 25;99(2):e0147224. doi: 10.1128/jvi.01472-24. Epub 2025 Jan 24.
Pseudorabies virus (PRV) is a porcine neurotropic alphaherpesvirus that infects peripheral tissues of its host, spreads into the nervous system, and establishes a life-long latency in neuronal cells. During productive infection, PRV replicates rapidly and causes pseudorabies or Aujeszky's disease. Reactivation from latent infection in the nervous system may lead to anterograde axonal transport of progeny virions, leading to recurrent infection of the epithelial layer and virus spread. Dexamethasone (DEX), a member of the glucocorticoid family that is widely used in clinical treatment as a high-efficiency glucocorticoid receptor (GR) agonist, is known to trigger reactivation of alphaherpesviruses like PRV and the closely related bovine alphaherpesvirus 1. In the current study, two cell type-dependent distinct regulatory mechanisms of glucocorticoid during PRV infection are described. In neuron-like cells, DEX upregulates expression of PRV IE180 and promotes viral productive infection. In addition, we found that GR activates the IE180 promoter by binding multiple GR response elements. The amino acids A465, P631, and I634 in GR were found to be critical for IE180 promoter activation. The impact of DEX on PRV productive infection in epithelial cells was also investigated. Interestingly, DEX was found to downregulate IE180 expression and suppress PRV infection in epithelial cells. Mechanistically, in epithelial cells, activation of the IE180 promoter by the VP16/Oct-1 (octamer-binding transcription factor 1) complex was suppressed by DEX-mediated degradation of Oct-1 in epithelial cells. In summary, our work reveals two distinct, cell type-dependent biological functions of glucocorticoid during PRV infection in neuron-like and epithelial cells, respectively.IMPORTANCEPseudorabies virus (PRV) can infect mucosal epithelium and the peripheral nervous system of its host, resulting in acute infection in epithelial cells and neuronal cells. In this study, we describe that glucocorticoid promotes PRV replication in neuron-like cells while it suppresses productive infection in epithelial cells through distinct regulations of the viral transactivator IE180, thereby revealing a cell type-dependent regulatory mechanism of glucocorticoid on PRV infection. Therefore, our findings provide a new perspective on the role of glucocorticoids during PRV infection.
伪狂犬病病毒（PRV）是一种嗜神经性猪α疱疹病毒，可感染宿主的外周组织，扩散至神经系统，并在神经元细胞中建立终身潜伏感染。在增殖性感染期间，PRV迅速复制并引发伪狂犬病或奥耶斯基氏病。神经系统潜伏感染的重新激活可能导致子代病毒粒子的顺行轴突运输，从而导致上皮层的反复感染和病毒传播。地塞米松（DEX）是糖皮质激素家族的一员，作为一种高效的糖皮质激素受体（GR）激动剂广泛应用于临床治疗，已知其可触发PRV等α疱疹病毒以及密切相关的牛α疱疹病毒1的重新激活。在本研究中，描述了糖皮质激素在PRV感染期间两种细胞类型依赖性的不同调节机制。在类神经元细胞中，DEX上调PRV IE180的表达并促进病毒的增殖性感染。此外，我们发现GR通过结合多个GR反应元件激活IE180启动子。发现GR中的氨基酸A465、P631和I634对IE180启动子激活至关重要。还研究了DEX对上皮细胞中PRV增殖性感染的影响。有趣的是，发现DEX下调上皮细胞中IE180的表达并抑制PRV感染。机制上，在上皮细胞中，DEX介导的上皮细胞中Oct-1的降解抑制了VP16/Oct-1（八聚体结合转录因子1）复合物对IE180启动子的激活。总之，我们的工作揭示了糖皮质激素在PRV感染期间在类神经元细胞和上皮细胞中分别具有两种不同的、细胞类型依赖性的生物学功能。
重要性
伪狂犬病病毒（PRV）可感染其宿主的粘膜上皮和外周神经系统，导致上皮细胞和神经元细胞的急性感染。在本研究中，我们描述了糖皮质激素通过对病毒反式激活因子IE180的不同调节促进类神经元细胞中PRV的复制，同时抑制上皮细胞中的增殖性感染，从而揭示了糖皮质激素对PRV感染的细胞类型依赖性调节机制。因此，我们的发现为糖皮质激素在PRV感染期间的作用提供了新的视角。
