The Molecular Pathogenesis of Varicella Zoster Virus Infection

描述（由申请人提供）：本计划项目（PPG）的目标是预防由普遍存在的高度嗜神经性水痘带状疱疹病毒（VZV）重新激活引起的老年人严重神经系统疾病。该项目包括3个科学项目和支助性行政和科学核心。水痘带状疱疹病毒（VZV）的原发性感染通常引起水痘，之后病毒潜伏在沿着整个神经轴的神经节神经元中。随着年龄的增长，细胞介导的对VZV的免疫力下降导致病毒重新激活，表现为带状疱疹（带状疱疹），其特征在于疼痛和皮疹仅限于1-3个皮区。带状疱疹的发病率和严重程度在器官移植接受者和癌症或艾滋病患者中也会增加。带状疱疹常并发慢性疼痛（带状疱疹后神经痛）、瘫痪、失明和中风。目前，每年约有1，000，000名美国人患带状疱疹。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，每年仍会发生> 50万例病例。该PPG将：确定多灶性VZV血管病变作为老年人视力丧失和头痛的重要原因的新作用，检查VZV退出潜伏期导致疾病的机制，并确定参与免疫和感染传播的关键病毒-宿主相互作用。项目1，一个令人兴奋的新的翻译项目，将确定临床，实验室和 一种多灶性VZV血管病变的病理特征，类似于巨细胞动脉炎（GCA），是老年人视力丧失和头痛的原因，这些发现可能会改变当前的临床实践模式。项目2检验了VZV再激活最初涉及潜伏基因转录的普遍失调，随后是有利于病毒DNA复制和释放感染性病毒的条件的假设。项目3使用动物模型来确定有助于病毒发病机制的关键病毒-宿主免疫细胞相互作用。联合研究将提供诊断和治疗一种类似巨细胞动脉炎的多灶性VZV血管病变所需的有价值的临床、实验室和病理学数据，并将为预防导致VZV再激活的级联事件提供所需的分子基础，VZV再激活是严重神经系统疾病的原因，特别是在迅速增加的老年人和免疫功能低下的人群中。该提案融合了医学博士，博士和DVM在临床神经学，分子病毒学和免疫学方面的专业知识的技能和策略。

DESCRIPTION (Provided by applicant): The goal of this program project (PPG) is to prevent serious neurological disease in the elderly caused by reactivation of the ubiquitous highly neurotropic varicella zoster virus (VZV). The PPG contains 3 scientific projects and supportive administrative and scientific cores. Primary infection by varicella zoster virus (VZV) usually causes varicella, after which virus becomes latent in 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 increased in organ transplant recipients and patients with cancer or AIDS. Zoster is frequently complicated by chronic pain (postherpetic neuralgia), 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 would still occur every year. This PPG will: determine the emerging role of multifocal VZV vasculopathy as an important cause of vision loss and headaches in the elderly, examine mechanisms by which VZV exits latency to cause disease and identify key virus-host interactions involved in immunity and spread of infection. Project 1, an exciting new translational project, will identify clinical, laboratory and pathological features of a form of multifocal VZV vasculopathy that mimics giant cell arteritis (GCA), a cause of vision loss and headache in the elderly, findings that are likely to shift the current clinical practice paradigm. Project 2 tests the hypothesis that VZV reactivation initially involves generalized deregulation of latent gene transcription followed by conditions conducive to virus DNA replication and release of infectious virus. Project 3 uses an animal model to determine critical virus-host immune cell interactions that contribute to viral pathogenesis. The combined studies will provide valuable clinical, laboratory and pathological data needed to diagnose and treat a form of multifocal VZV vasculopathy that mimics giant cell arteritis and will provide the needed molecular groundwork for efforts to prevent the cascade of events leading to 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 MDs, PhDs and DVMs with expertise in clinical neurology, molecular virology and immunology.