Zerboni Leigh, Arvin Ann
Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America.
Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America; Departments of Pediatrics and Microbiology & Immunology, Stanford University School of Medicine, Stanford, California, United States of America.
PLoS Pathog. 2015 Jun 19;11(6):e1004989. doi: 10.1371/journal.ppat.1004989. eCollection 2015 Jun.
Varicella zoster virus (VZV), a human alphaherpesvirus, causes varicella during primary infection. VZV reactivation from neuronal latency may cause herpes zoster, post herpetic neuralgia (PHN) and other neurologic syndromes. To investigate VZV neuropathogenesis, we developed a model using human dorsal root ganglia (DRG) xenografts in immunodeficient (SCID) mice. The SCID DRG model provides an opportunity to examine characteristics of VZV infection that occur in the context of the specialized architecture of DRG, in which nerve cell bodies are ensheathed by satellite glial cells (SGC) which support neuronal homeostasis. We hypothesized that VZV exhibits neuron-subtype specific tropism and that VZV tropism for SGC contributes to VZV-related ganglionopathy. Based on quantitative analyses of viral and cell protein expression in DRG tissue sections, we demonstrated that, whereas DRG neurons had an immature neuronal phenotype prior to implantation, subtype heterogeneity was observed within 20 weeks and SGC retained the capacity to maintain neuronal homeostasis longterm. Profiling VZV protein expression in DRG neurons showed that VZV enters peripherin+ nociceptive and RT97+ mechanoreceptive neurons by both axonal transport and contiguous spread from SGC, but replication in RT97+ neurons is blocked. Restriction occurs even when the SGC surrounding the neuronal cell body were infected and after entry and ORF61 expression, but before IE62 or IE63 protein expression. Notably, although contiguous VZV spread with loss of SGC support would be predicted to affect survival of both nociceptive and mechanoreceptive neurons, RT97+ neurons showed selective loss relative to peripherin+ neurons at later times in DRG infection. Profiling cell factors that were upregulated in VZV-infected DRG indicated that VZV infection induced marked pro-inflammatory responses, as well as proteins of the interferon pathway and neuroprotective responses. These neuropathologic changes observed in sensory ganglia infected with VZV may help to explain the neurologic sequelae often associated with zoster and PHN.
水痘带状疱疹病毒（VZV）是一种人类α疱疹病毒，在初次感染时引起水痘。VZV从神经元潜伏状态重新激活可能导致带状疱疹、疱疹后神经痛（PHN）和其他神经综合征。为了研究VZV神经发病机制，我们开发了一种在免疫缺陷（SCID）小鼠中植入人背根神经节（DRG）异种移植物的模型。SCID DRG模型为研究VZV感染特征提供了一个机会，这种感染发生在DRG的特殊结构背景下，其中神经细胞体被支持神经元稳态的卫星神经胶质细胞（SGC）包裹。我们假设VZV表现出神经元亚型特异性嗜性，并且VZV对SGC的嗜性导致与VZV相关的神经节病。基于对DRG组织切片中病毒和细胞蛋白表达的定量分析，我们证明，虽然DRG神经元在植入前具有未成熟的神经元表型，但在20周内观察到亚型异质性，并且SGC长期保留维持神经元稳态的能力。对DRG神经元中VZV蛋白表达的分析表明，VZV通过轴突运输和从SGC的连续扩散进入外周蛋白阳性伤害性神经元和RT97阳性机械感受神经元，但在RT97阳性神经元中的复制被阻断。即使神经元细胞体周围的SGC被感染并且在进入和ORF61表达之后，但在IE62或IE63蛋白表达之前，限制就会发生。值得注意的是，尽管预计VZV与SGC支持丧失的连续扩散会影响伤害性和机械感受神经元的存活，但在DRG感染后期，RT97阳性神经元相对于外周蛋白阳性神经元表现出选择性丧失。对VZV感染的DRG中上调的细胞因子进行分析表明，VZV感染诱导了明显的促炎反应，以及干扰素途径和神经保护反应的蛋白。在感染VZV的感觉神经节中观察到的这些神经病理变化可能有助于解释通常与带状疱疹和PHN相关的神经后遗症。
