Acute Simian Varicella Virus Infection Causes Robust and Sustained Changes in Gene Expression in the Sensory Ganglia
Acute Simian Varicella Virus Infection Causes Robust and Sustained Changes in Gene Expression in the Sensory Ganglia
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DOI：
10.1128/jvi.01272-16
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发表时间：
2016-12-01
影响因子：
5.4
通讯作者：
Messaoudia, Ilhem
中科院分区：
文献类型：
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作者：
Arnold, Nicole;Girke, Thomas;Messaoudia, Ilhem
水痘-带状疱疹病毒(VZV)是一种嗜神经性的甲型疱疹病毒，初次感染会导致水痘。VZV在感觉神经节中建立潜伏期，并可能在以后的生活中重新激活，导致带状疱疹。由于临床标本的获取有限，感觉神经节急性感染期间VZV与宿主之间的关系尚不清楚。恒河猴支气管内接种猴水痘病毒(SVV)重现了人类感染VZV的特征。我们利用这个动物模型，通过测量感染后3天、7天、10天、14天和100天的病毒和宿主转录，来表征急性和潜伏感染期间神经节中宿主-病原体的相互作用。在皮疹出现前3dpi的感觉神经节内可检测到SVV DNA和转录本。3dpi感觉神经节内也可检测到CD4和CD8T细胞。此外，从同一动物3dpi分离的驻肺T细胞也含有SVV DNA和转录本，这表明T细胞可能负责将SVV运输到神经节。转录组测序(RNA-Seq)分析表明，病毒转录7dpi的停止与神经节内强大的抗病毒先天免疫反应相一致。有趣的是，在神经系统发育和功能中起关键作用的大量基因仍然被下调到潜伏期。这些研究为急性水痘期间感觉神经节内宿主和病原体的相互作用提供了新的见解，并证明了SVV感染导致神经元基因表达的深刻和持续的变化。重要信息由于获得人类标本的有限以及VZV严格意义上是人类病毒的事实，VZV感染感觉神经节的许多方面仍然知之甚少。恒河猴感染猴水痘病毒(SVV)，是VZV的同源物，为人类疾病提供了一个可靠的模型。使用这个模型，我们证明了SVV在感染后早期到达神经节，很可能是通过T细胞，并且诱导强大的先天免疫反应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仍会持续很长时间。鉴于SVV和VZV之间的同源性，以及恒河猴和人类之间的遗传和生理相似之处，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感染的一些神经系统后果。
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.IMPORTANCEMany 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.