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

• 批准号: 7766223
• 负责人: DONALD GILDEN
• 金额: $ 162.08万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7766223
• 关键词: molecular; pathogenesis; varicella; zoster; virus

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）：该计划项目的目的是了解人神经节中高度神经性水痘带状疱疹病毒（VZV）的潜在状态与病毒重新激活产生的急性和慢性神经疾病的发展。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）的原发性感染通常会引起水痘（水痘），此后，病毒在整个神经神经元的人神经节神经元中变得潜在。随着衰老的衰老，对VZV的细胞介导的免疫力下降会导致病毒重新激活，表现为疱疹带状疱疹（带状疱疹），其特征是疼痛，皮疹限制在1-3个皮肤上。带领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。带状疱疹经常因慢性疼痛（后神经痛）以及瘫痪，失明和中风而复杂。目前，每年约有1,000,000名美国人发育Zoster。 OKA VZV疫苗将带领的发病率降低了50％，但是即使为60岁以上的每个美国人接种疫苗，> 500,000例带状疱疹仍将发生。该程序项目仅集中于原发性VZV感染，潜伏期和重新激活的分子发病机理。项目1研究在神经元的VZV感染期间，病毒和细胞蛋白抑制细胞凋亡，导致神经元存活和病毒潜伏期。 项目2研究神经节中VZV潜伏期和重新激活的分子机制，重点是VZV IE63，VZV IE63，这是在潜在地感染的人神经节中鉴定出的最普遍和最丰富的转录本的蛋白质产物，其从细胞质转移到核可能会改变IE63功能并诱导病毒重新激活。项目3研究了动物模型中水痘的免疫生物学，重点是鉴定宿主细胞类型及其在原发性感染和细胞因子表达以及水痘染色体中细胞因子表达以及病毒特异性T细胞中皮肤和神经节中的水痘感染中的作用。对潜在和重新激活的VZV和Simian Vericella病毒（SVV）的物理状态的全面了解将为防止导致人类VZV重新激活的事件的策略提供理性的基础，这是严重的神经系统疾病的原因，尤其是在快速增长的原因老年人和免疫功能低下的人群。该建议融合了研究人​​员在临床神经病学，病毒学，分子和细胞生物学以及临床研究方面具有专业知识的研究者的技能和策略。