The Molecular Pathogenesis of Varicella Zoster Virus Infection

水痘带状疱疹病毒感染的分子发病机制

基本信息

批准号：
8608702
负责人：
DONALD GILDEN
金额：
$ 196.85万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8608702
关键词：
Acquired Immunodeficiency Syndrome Acute Adrenal Cortex Hormones Adult Age Aging American Animal Model Antiviral Agents Biopsy Blindness Blood C-reactive protein CD8B1 gene Cell Communication Cells Cellular Immunity Chickenpox Clinical DNA biosynthesis Data Development Diagnosis Disease Elderly Event Exanthema Flow Cytometry Ganglia Gene Expression Profile Genes Genetic Transcription Genome Goals Headache Health Herpes zoster disease Herpesviridae Herpesvirus Type 3 Human Immune Immune response Immunity Immunocompromised Host Incidence Infection Jaw Laboratories Lead Lung Malignant Neoplasms Methods Modeling Molecular Molecular Immunology Molecular Virology Monkeys Morbidity - disease rate Myalgia Neuraxis Neurologic Neurology Neurons Organ Organ Transplantation Pain Paralysed Pathogenesis Pathway interactions Patients Population Postherpetic neuralgia Process Role Sedimentation process Severities Steroids Stroke T-Lymphocyte Temporal Arteries Temporal Arteritis Testing Therapeutic Intervention Tissues Translating Transplant Recipients Vaccinated Vaccines Vascular Diseases Viral Pathogenesis Virus Virus Diseases Virus Latency base cell type chronic neurologic disease chronic pain claudication clinical practice design innovation lymph nodes mortality nervous system disorder neurotropic novel prevent programs reactivation from latency skills success viral DNA virus host interaction virus pathogenesis

项目摘要

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.

描述（由申请人提供）：该计划项目（PPG）的目标是预防老年人因普遍存在的高度嗜神经性水痘带状疱疹病毒（VZV）重新激活而引起的严重神经系统疾病。 PPG 包含 3 个科学项目以及支持性行政和科学核心。水痘带状疱疹病毒（VZV）的初次感染通常会引起水痘，此后病毒潜伏在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），其特征是疼痛和仅限于 1-3 个皮节的皮疹。器官移植受者以及癌症或艾滋病患者的带状疱疹发病率和严重程度也会增加。带状疱疹常常并发慢性疼痛（带状疱疹后神经痛）、瘫痪、失明和中风。目前，每年有-1,000,000 名美国人患上带状疱疹。 Oka VZV 疫苗可将带状疱疹的发病率降低 50%，但即使每个 60 岁以上的美国人都接种疫苗，每年仍会发生超过 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与宿主相互作用。项目 1 是一个令人兴奋的新转化项目，将确定临床、实验室和一种类似于巨细胞动脉炎（GCA）的多灶性 VZV 血管病的病理特征，巨细胞动脉炎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范式。项目 2 检验了以下假设：VZV 重新激活最初涉及潜伏基因转录的普遍失调，随后出现有利于病毒 DNA 复制和感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发病机制的关键病毒-宿主免疫细胞相互作用。联合研究将为诊断和治疗一种类似于巨细胞动脉炎的多灶性 VZV 血管病变提供所需的有价值的临床、实验室和病理数据，并将为防止导致 VZV 重新激活的级联事件提供所需的分子基础。严重的神经系统疾病，特别是在迅速增加的老年人和免疫功能低下的人群中。该提案将医学博士、博士和兽医学博士的技能和策略与临床神经学、分子病毒学和免疫学方面的专业知识融为一体。