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：
8458407
负责人：
DONALD GILDEN
金额：
$ 9.72万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8458407
关键词：
Acquired Immunodeficiency Syndrome Acute Age Aging American Animal Model Blindness Cell Nucleus Cellular Immunity Cellular biology Chickenpox Clinical Clinical Trials Cytoplasm Development Disease Elderly Event Exanthema Ganglia Goals Herpes zoster disease Herpesvirus Type 3 Human Immunobiology Immunocompromised Host Incidence Infection Inhibition of Apoptosis Knowledge Malignant Neoplasms Molecular Molecular Biology Neuraxis Neurologic Neurology Neurons Pain Paralysed Pathogenesis Patients Population Postherpetic neuralgia Proteins Research Personnel Role Severities Skin Stroke T-Lymphocyte Transcript Transplant Recipients Vaccinated Vaccines Viral Virus Virus Activation Virus Diseases Virus Latency cell type chronic neurologic disease chronic pain cytokine neuronal survival neurotropic physical state prevent programs reactivation from latency skills virology

项目摘要

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.

描述（由申请人提供）：该项目的目标是了解人类神经节中高度嗜神经性水痘带状疱疹病毒（VZV）的潜伏状态与病毒重新激活引起的急性和慢性神经系统疾病的发展之间的关系。该计划项目包含一个行政核心、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），此后病毒潜伏在整个神经轴的人类神经节神经元中。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。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。带状疱疹经常并发慢性疼痛（带状疱疹后神经痛）以及瘫痪、失明和中风。目前，每年约有 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了疫苗，每年仍会发生超过 50 万例带状疱疹病例。该项目专门研究原发性水痘带状疱疹病毒感染、潜伏期和再激活的分子发病机制。项目 1 研究在 VZV 感染神经元期间病毒和细胞蛋白抑制细胞凋亡，从而导致神经元存活和病毒潜伏期。项目2研究神经节中VZV潜伏和重新激活的分子机制，重点关注VZV IE63，这是在潜伏感染的人类神经节中发现的最普遍和最丰富的转录物的蛋白质产物，其从细胞质易位到细胞核可能导致IE63功能改变和诱导病毒重新激活。项目3研究动物模型中的水痘免疫生物学，重点是宿主细胞类型的鉴定及其在初次感染期间皮肤和神经节中水痘感染的运输和建立中的作用以及水痘再激活中的细胞因子表达和病毒特异性T细胞。对潜伏和重新激活的 VZV 和猿水痘病毒 (SVV) 物理状态的全面了解将为制定策略提供合理的基础，以防止导致人类 VZV 重新激活的级联事件，这是严重神经系统疾病的原因，特别是在迅速增加的神经系统疾病中。老年人和免疫功能低下的人群。该提案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研究专业知识的研究人员的技能和策略。