Varicella zoster virus-Induced Pain in a Rat Model of Post-Herpetic Neuralgia

描述（由申请人提供）：带状疱疹后神经痛（PHN）是带状疱疹的一种常见且极其痛苦的并发症，它使人衰弱、顽固、持久且难以治疗。 PHN 随着年龄的增长而急剧增加，因此是一种可能严重降低生活质量的老年人疾病。鉴于社会老龄化，PHN 将成为一个更加紧迫的公共卫生问题。当人类疱疹病毒、水痘带状疱疹病毒 (VZV) 从水痘期间在宿主感觉神经元中建立的潜伏状态重新激活时，就会发生带状疱疹和 PHN。虽然病毒复制会引起神经损伤和炎症从而引发疼痛，但水痘带状疱疹病毒引起持续性疼痛的机制尚不清楚。该项目针对 FOA PA-07-282，并将集中于 VZV 引起的疼痛的新的临床相关模型，其中将人 VZV 注射到大鼠后爪后会出现长时间的痛觉过敏和异常性疼痛。该提案的基本假设是，通过使用这种新的大鼠模型，我们将能够更好地理解 VZV 如何与初级传入系统相互作用以诱发疼痛，并测试新的基因治疗方法来治疗 VZV 诱发的疼痛。在具体目标 1 中，我们将使用一组全面的抗体，通过表征 VZV 诱导伤害感受之前、期间和之后背根神经节 (DRG) 感觉神经元中的病毒和疼痛标记蛋白表达来检查大鼠 VZV 感染的生物学。我们将确定每个阶段 DRG 中表达的 VZV 蛋白，并确定病毒基因表达模式是否与疼痛反应和恢复相关。我们还将鉴定表达 VZV 抗原的神经元类型，并确定它们是否在 DRG 和脊髓处表现出神经性和/或炎性疼痛标记物的上调。这项工作将建立模型中潜在的 VZV 生物学，以及疼痛反应是否是感染过程的结果，与人类 VZV 裂解性感染或 VZV 潜伏期相似。在具体目标 2 中，我们将通过测试以下能力来询问哪些特定的 VZV 蛋白是诱导疼痛所必需的：1) 各种突变型 VZV 重组体，每种重组体都在特定的调节病毒基因中进行了改变；2) 各种 HSV 载体，每种载体都构建为表达单个 VZV 调节基因，以诱导伤害感受。这可能会识别出特定的 VZV 蛋白，以便在制定抗疼痛策略时进一步靶向，并可能导致改进疫苗，而无需诱导 PHN。第三个具体目标是通过测试 HSV 载体介导的疼痛调节剂递送可以减少 VZV 引起的异常性疼痛和痛觉过敏的假设来探索新的治疗途径。我们将研究使用表达脑啡肽原、GAD、甘氨酸受体和抗炎蛋白的 HSV 载体来治疗模型中 VZV 诱导的超敏反应，所有这些都已被证明可以减轻其他系统的疼痛。总之，对该模型的探索可能有助于了解水痘带状疱疹病毒产生疼痛的细胞变化，这不仅会增加对水痘带状疱疹病毒感染中病原体与宿主相互作用的了解，而且可能有助于开发治疗干预的新分子靶点。该项目研究一种由疱疹病毒水痘带状疱疹病毒引起的新疼痛模型，该模型反映了一种常见且高度衰弱的人类老年人疾病——带状疱疹后神经痛（PHN）。对模型的检查可能会确定开发抗疼痛策略的新目标，并可能导致鉴定出无法引起疼痛的改进候选疫苗。该项目还可能确定使用基因治疗方法减轻 PHN 的新方法。

DESCRIPTION (provided by applicant): Post-Herpetic Neuralgia (PHN) is a common and exceedingly painful complication of herpes zoster that is debilitating, intractable, long-lasting and difficult to treat. PHN increases dramatically with age, and is thus a disease of the elderly which may profoundly reduce the quality of life. Given the aging nature of our society, PHN will become an even more pressing public health concern. Zoster and PHN occur when the human herpesvirus, varicella-zoster virus (VZV), reactivates from a latent state that was established in the host sensory neurons during chickenpox. While viral replication induces nerve damage and inflammation to initiate pain, the mechanisms by which VZV causes persistent pain are not well understood. This project is directed to FOA PA-07-282, and will center on a new clinically relevant model of VZV-induced pain in which prolonged hyperalgesia and allodynia occur following injection of human VZV into the rat hindpaw. The overlying hypothesis of this proposal is that by using this new rat model we will be able to better comprehend how VZV interacts with the primary afferent system to induce pain and test novel gene therapy approaches to treat VZV induced pain. In Specific Aim 1, we will examine the biology of VZV infection in the rat by characterizing viral and pain marker protein expression in the dorsal root ganglion (DRG) sensory neurons before, during and after VZV-induced nociception, using a comprehensive panel of antibodies. We will determine which VZV proteins are expressed in the DRG at each stage and address if viral gene expression patterns correlate with the pain response and recovery from it. We will also identify types of neurons expressing VZV antigens and determine if they display an upregulation of markers of neuropathic and/or inflammatory pain at both the DRG and the spinal cord. This work will establish the underlying VZV biology in the model and whether the pain response is a result of an infectious process with similarities to human VZV lytic infections or to VZV latency. In Specific aim 2, we will ask what specific VZV proteins are necessary to induce pain by testing the ability of: 1) various mutant VZV recombinants, each altered in a specific regulatory viral gene, and 2) various HSV vectors, each constructed to express a single VZV regulatory gene, to induce nociception. This may identify specific VZV proteins for further targeting in developing anti-pain strategies, and may lead to improved vaccines without the ability to induce PHN. The third specific aim will explore new avenues of treatment by testing the hypothesis that HSV vector-mediated delivery of modulators of pain can reduce the allodyna and hyperalgesia induced by VZV. We will investigate the use of HSV vectors expressing pro-enkephalin, GAD, the glycine receptor, and anti inflammatory proteins to treat VZV-induced hypersensitivity in the model, all of which have been shown to reduce pain in other systems. Together, exploration of this model may lead to an understanding of cellular changes that may underlie the generation of pain by VZV that will not only add to knowledge of pathogen:host interactions in VZV infection, but may help in developing new molecular targets for therapeutic intervention. This project studies a new model of pain induced by the herpesvirus varicella zoster virus that is reflective of a common and highly debilitating human disease of the elderly, post herpetic neuralgia (PHN). The examination of the model may identify new targets for the development of anti-pain strategies, and may lead to the identification of improved vaccine candidates that are unable to induce pain. The project may also identify new methods to alleviate PHN using gene therapy approaches.