The Molecular Pathogenesis of Varicella Zoster Virus Infection

描述(申请人提供)：该计划项目(PPG)的目标是预防由普遍存在的高度嗜神经的水痘带状疱疹病毒(VZV)重新激活而导致的老年人严重的神经系统疾病。PPG包括3个科学项目以及支持性的行政和科学核心。水痘带状疱疹病毒(VZV)的初次感染通常引起水痘，之后病毒潜伏在沿整个神经轴的神经节神经元中。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。在器官移植受者和癌症或艾滋病患者中，带状疱疹的发病率和严重程度也会增加。带状疱疹通常伴有慢性疼痛(带状疱疹后神经痛)、瘫痪、失明和中风。目前，每年有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。这项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出现的作用，检查VZV潜伏期导致疾病的机制，并确定涉及免疫和感染传播的关键病毒-宿主相互作用。项目1是一个令人兴奋的新翻译项目，将确定临床、实验室和 一种类似于巨细胞性动脉炎(GCA)的多灶性VZV血管病变的病理特征，GCA是老年人视力丧失和头痛的原因，这一发现可能会改变当前的临床实践范式。项目2测试了这样的假设，即VZV的重新激活最初涉及对潜伏基因转录的普遍放松，随后是有利于病毒DNA复制和传染性病毒释放的条件。项目3使用动物模型来确定导致病毒致病的关键病毒-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血管病变所需的宝贵的临床、实验室和病理学数据，并将为努力防止导致VZV重新激活的一连串事件提供必要的分子基础，VZV重新激活是导致严重神经疾病的原因，特别是在迅速增加的老年人和免疫功能受损的人群中。这项建议将医学博士、博士和数字视频管理人员的技能和策略与临床神经学、分子病毒学和免疫学的专业知识相结合。

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.