The molecular pathogenesis of varicella zoster virus infection

描述(申请人提供)：本项目的目标是了解高度嗜神经性水痘带状疱疹病毒(VZV)在人类神经节中的潜伏状态与病毒重新激活引起的急慢性神经系统疾病的发展之间的关系。该计划项目包括一个行政核心、一个科学核心和3个科学项目。水痘带状疱疹病毒(VZV)的初次感染通常会引起水痘(水痘)，之后病毒潜伏在沿整个神经轴的人神经节神经元中。随着年龄的增长，对VZV的细胞免疫功能下降会导致病毒重新激活，表现为带状疱疹(带状疱疹)，其特征是疼痛和皮疹局限于1-3个皮肤体。带状疱疹的发病率和严重程度在移植受者和癌症或艾滋病患者中也很高。带状疱疹经常伴有慢性疼痛(带状疱疹后神经痛)，以及瘫痪、失明和中风。目前，每年约有100万美国人罹患带状疱疹。Oka VZV疫苗将带状疱疹的发病率降低了50%，但即使每个60岁以上的美国人都接种了疫苗，每年仍将发生50万例带状疱疹病例。该计划项目专门关注VZV原发感染、潜伏和重新激活的分子发病机制。项目1研究病毒和细胞蛋白在VZV感染神经元期间抑制细胞凋亡，从而导致神经元存活和病毒潜伏期。 项目2研究VZV在神经节中潜伏和重新激活的分子机制，重点是VZV IE63，这是在潜伏感染的人类神经节中发现的最普遍和丰富的转录本的蛋白产物，其从细胞质到细胞核的移位可能导致IE63功能的改变和诱导病毒重新激活。项目3在动物模型中研究水痘的免疫生物学，重点是鉴定宿主细胞类型及其在水痘初次感染期间皮肤和神经节内水痘感染的运输和建立中的作用，以及水痘重新激活过程中细胞因子和病毒特异性T细胞的表达。对潜伏和重新激活的VZV和猴水痘病毒(SVV)的物理状态的全面了解将为预防导致人类VZV重新激活的一连串事件提供合理的基础，VZV重新激活是严重的神经系统疾病的原因，特别是在迅速增长的老年和免疫功能低下的人群中。这项建议融合了具有临床神经学、病毒学、分子和细胞生物学以及临床调查专业知识的研究人员的技能和策略。

DESCRIPTION (provided by applicant): The goal of this program project is to understand the relationship between the latent state of the highly neurotropic varicella zoster virus (VZV) in human ganglia and the development of acute and chronic neurologic disease produced by virus reactivation. The program project contains an administrative core, a scientific core and 3 scientific projects. Primary infection by varicella zoster virus (VZV) usually causes varicella (chickenpox), after which virus becomes latent in human ganglionic neurons along the entire neuraxis. With aging, a declining cell-mediated immunity to VZV leads to virus reactivation, manifesting as herpes zoster (shingles) characterized by pain and rash restricted to 1-3 dermatomes. The incidence and severity of zoster is also high in transplant recipients and patients with cancer or AIDS. Zoster is frequently complicated by chronic pain (postherpetic neuralgia), as well as paralysis, blindness and stroke. Currently, ~1,000,000 Americans develop zoster annually. Oka VZV vaccine reduces the incidence of zoster by 50%, but even if every American over age 60 was vaccinated, >500,000 cases of zoster would still occur every year. This program project is focused exclusively on the molecular pathogenesis of primary VZV infection, latency and reactivation. Project 1 studies inhibition of apoptosis by both viral and cellular proteins during VZV infection of neurons that results in neuronal survival and viral latency. Project 2 studies molecular mechanisms of VZV latency and reactivation in ganglia, focusing on VZV IE63, the protein product of the most prevalent and abundant transcript identified in latently infected human ganglia, and whose translocation from the cytoplasm to the nucleus may result in altered IE63 function and induction of virus reactivation. Project 3 studies the immunobiology of varicella in an animal model, focusing on identification of host cell types and their role in transport and establishment of varicella infection in skin and ganglia during primary infection and cytokine expression and virus-specific T cells in varicella reactivation. A comprehensive knowledge of the physical state of latent and reactivated VZV and simian varicella virus (SVV) will provide the rational underpinning for strategies to prevent the cascade of events leading to human VZV reactivation, a cause of serious neurologic disease, particularly in the rapidly increasing elderly and immunocompromised populations. This proposal melds the skills and strategies of investigators with expertise in clinical neurology, virology, molecular and cell biology and clinical investigation.