Arnold Nicole, Girke Thomas, Sureshchandra Suhas, Messaoudi Ilhem
Graduate Program in Microbiology, University of California-Riverside, Riverside, California, USA.
Department of Botany and Plant Sciences, University of California-Riverside, Riverside, California, USA.
J Virol. 2016 Nov 14;90(23):10823-10843. doi: 10.1128/JVI.01272-16. Print 2016 Dec 1.
Primary infection with varicella-zoster virus (VZV), a neurotropic alphaherpesvirus, results in varicella. VZV establishes latency in the sensory ganglia and can reactivate later in life to cause herpes zoster. The relationship between VZV and its host during acute infection in the sensory ganglia is not well understood due to limited access to clinical specimens. Intrabronchial inoculation of rhesus macaques with simian varicella virus (SVV) recapitulates the hallmarks of VZV infection in humans. We leveraged this animal model to characterize the host-pathogen interactions in the ganglia during both acute and latent infection by measuring both viral and host transcriptomes on days postinfection (dpi) 3, 7, 10, 14, and 100. SVV DNA and transcripts were detected in sensory ganglia 3 dpi, before the appearance of rash. CD4 and CD8 T cells were also detected in the sensory ganglia 3 dpi. Moreover, lung-resident T cells isolated from the same animals 3 dpi also harbored SVV DNA and transcripts, suggesting that T cells may be responsible for trafficking SVV to the ganglia. Transcriptome sequencing (RNA-Seq) analysis showed that cessation of viral transcription 7 dpi coincides with a robust antiviral innate immune response in the ganglia. Interestingly, a significant number of genes that play a critical role in nervous system development and function remained downregulated into latency. These studies provide novel insights into host-pathogen interactions in the sensory ganglia during acute varicella and demonstrate that SVV infection results in profound and sustained changes in neuronal gene expression.
Many aspects of VZV infection of sensory ganglia remain poorly understood, due to limited access to human specimens and the fact that VZV is strictly a human virus. Infection of rhesus macaques with simian varicella virus (SVV), a homolog of VZV, provides a robust model of the human disease. Using this model, we show that SVV reaches the ganglia early after infection, most likely by T cells, and that the induction of a robust innate immune response correlates with cessation of virus transcription. We also report significant changes in the expression of genes that play an important role in neuronal function. Importantly, these changes persist long after viral replication ceases. Given the homology between SVV and VZV, and the genetic and physiological similarities between rhesus macaques and humans, our results provide novel insight into the interactions between VZV and its human host and explain some of the neurological consequences of VZV infection.
原发性水痘带状疱疹病毒（VZV）感染，一种嗜神经性α疱疹病毒，会导致水痘。VZV在感觉神经节中建立潜伏状态，并可能在日后重新激活引发带状疱疹。由于获取临床标本受限，VZV与宿主在感觉神经节急性感染期间的关系尚不清楚。用猴水痘病毒（SVV）对恒河猴进行支气管内接种可重现人类VZV感染的特征。我们利用这个动物模型，通过在感染后第3、7、10、14和100天测量病毒和宿主转录组，来表征急性和潜伏感染期间神经节中的宿主 - 病原体相互作用。在皮疹出现前3天，在感觉神经节中检测到SVV DNA和转录本。在感染后3天，在感觉神经节中也检测到CD4和CD8 T细胞。此外，在感染后3天从同一动物分离的肺驻留T细胞也携带SVV DNA和转录本，表明T细胞可能负责将SVV转运至神经节。转录组测序（RNA - Seq）分析表明，感染后7天病毒转录停止与神经节中强烈的抗病毒先天免疫反应同时发生。有趣的是，许多在神经系统发育和功能中起关键作用的基因在潜伏期间仍保持下调状态。这些研究为急性水痘期间感觉神经节中的宿主 - 病原体相互作用提供了新的见解，并表明SVV感染导致神经元基因表达发生深刻且持续的变化。
由于获取人类标本受限以及VZV严格来说是一种人类病毒，VZV感染感觉神经节的许多方面仍知之甚少。用VZV的同源物猴水痘病毒（SVV）感染恒河猴提供了一个有力的人类疾病模型。利用这个模型，我们表明SVV在感染后早期到达神经节，很可能是通过T细胞，并且强烈的先天免疫反应的诱导与病毒转录的停止相关。我们还报告了在神经元功能中起重要作用的基因表达的显著变化。重要的是，这些变化在病毒复制停止后很长时间仍然存在。鉴于SVV与VZV的同源性以及恒河猴与人类之间的遗传和生理相似性，我们的结果为VZV与其人类宿主之间的相互作用提供了新的见解，并解释了VZV感染的一些神经学后果。
