Neurobiology of Varicella Zoster Virus

水痘带状疱疹病毒的神经生物学

• 批准号: 8979278
• 负责人: DONALD GILDEN
• 金额: $ 32.66万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8979278
• 关键词: 2' ,3' -Cyclic-Nucleotide Phosphodiesterases; Acquired Immunodeficiency Syndrome; Acyclovir; Affect; Aftercare; Age; American; Antiviral Agents; Autopsy; Biological Assay; Biological Models; Blindness; Cells; Cellular Immunity; Cessation of life; Chickenpox; Child; Chronic; DNA Viruses; Disease; Elderly; Epigenetic Process; Episome; Event; Exanthema; Ganglia; Gene Expression; Gene Expression Profile; Genetic Transcription; Glial Fibrillary Acidic Protein; Herpes zoster disease; Herpesvirus Type 3; Histones; Hour; Human; Immune; Immune system; Immunity; Immunization; Immunocompromised Host; In Vitro; Incidence; Individual; Infection; Interferons; Laboratories; Malignant Neoplasms; MicroRNAs; Modeling; Myelitis; Negative Staining; Neuraxis; Neurobiology; Neurologic; Neurons; Organ Transplantation; Pain; Paralysed; Patients; Population; Postherpetic neuralgia; Reverse Transcriptase Polymerase Chain Reaction; Severities; Staining method; Stains; Stroke; Testing; Time; Transcript; Transplant Recipients; Tubulin; Vaccinated; Vaccines; Vascular Diseases; Viral Genes; Viral Genome; Virus; Virus Latency; base; chromatin immunoprecipitation; chronic pain; cytokine; deep sequencing; epigenetic marker; epigenetic regulation; killings; physical state; prevent; public health relevance; tissue culture; viral DNA

 DESCRIPTION (provided by applicant): Varicella zoster virus (VZV) causes varicella (chickenpox) in billions of children worldwide annually, after which virus becomes latent in ganglionic neurons along the entire neuraxis. Decades later, VZV-specific cell-mediated immunity declines and virus reactivates, resulting in zoster (shingles), characterized by pain and rash restricted to 1-3 dermatomes. Zoster affects ~1 million Americans yearly and is often complicated by chronic radicular pain (postherpetic neuralgia, PHN) and other serious neurological (cerebellitis, myelitis and vasculopathy) and ocular disorders that collectively cause paralysis, blindness and death. By 2030, 22% of Americans (65 million people) will be >age 65, and the >85 population will triple to >8 million. The incidence and severity of zoster range from a natural decline in VZV-specific immunity with advancing age to more serious host immune deficits seen in organ transplant recipients and in patients with cancer and AIDS. Zoster vaccine reduces the incidence of zoster by 50% for up to 3 years, yet even immunization of everyone >age 60 still predicts 500,000 cases of zoster and 200,000 cases of PHN annually. Thus, as the elderly population increases, so does the incidence of zoster and its attendant neurological and ocular complications. After first proving in 1983 that VZV is latent in human ganglia, our subsequent analyses of >7,000 human ganglia from >900 randomly autopsied subjects revealed the presence of the entire virus genome in neurons, most likely maintained as a histone-coated episome with variable VZV DNA abundance, VZV transcription restricted to ORF63, and epigenetic regulation of VZV gene expression. To more precisely define the extent of viral gene expression and epigenetic markers on the latent VZV genome, we examined VZV-infected differentiated neurons, which remained viable in culture up to 3 weeks without a cytopathic effect; treatment of these neurons with interferon- ¿ significantly reduced viral gene expression. Thus, we hypothesize that neurons treated to limit VZV gene expression will yield a model system that recapitulates VZV transcription in latently infected human ganglionic neurons. To test our hypothesis, we will: treat VZV non-lytically infected neurons in vitro with antiviral agents and molecules produced by cells of the innate and adaptive immune systems and examine VZV gene expression by RT-PCR (Aim 1); determine the physical state of VZV DNA, VZV gene expression and epigenetic markers present on VZV genomes within non-lytically infected neurons after treatment with acyclovir and multiple cytokines (Aim 2). Developing a model of VZV latency in vitro will allow studies that would normally require acquisition of thousands of human ganglia. An in-depth understanding of how VZV resides long-term in latently infected human nerve cells is prerequisite to developing strategies that prevent the cascade of events leading to virus reactivation, a cause of serious neurologic disease and blindness, particularly in the rapidly increasing elderly and immunocompromised populations.

 描述（由适用提供）：水痘带状疱疹病毒（VZV）每年在全球数十亿个儿童中引起水痘（Chirinspox），此后，病毒在整个神经毒性的神经节神经元中变得潜在。几十年后，VZV特异性细胞介导的免疫抑制下降并重新激活，导致带状疱疹（带状疱疹），其特征在于疼痛，皮疹局限于1-3个皮肤病。带状拥抱者每年影响约100万美国人，通常会因慢性辐射疼痛（后神经胶质疼痛，PHN）和其他严重的神经系统（小脑炎，脊髓炎和血管性炎）和眼部疾病而变得复杂 瘫痪，失明和死亡。到2030年，22％的美国人（6500万人）年龄在65岁之间，> 85人口将达到三倍至800万。带领的事件和严重性范围从 VZV特异性免疫学的自然下降，随着器官移植受者以及癌症和艾滋病患者的更严重宿主免疫反应的年龄增长。系带疫苗在3年中最多将带领的事件降低了50％，但即使是60岁的每个人的免疫学仍然可以预测每年有500,000例带状疱疹和200,000例PHN病例。随着年龄较大的人口的增加，带领及其随之而来的神经和眼并发症的事件也随之增加。 After first providing in 1983 that VZV is latent in human ganglia, our subsequent analyses of >7,000 human ganglia from >900 randomly autopsied subjects revealed the presence of the entire virus genome in neurons, most likely maintained as a histone-coated episode with variable VZV DNA abstraction, VZV transcription restricted to ORF63, and epigenetic regulation of VZV gene expression.为了更精确地定义潜在VZV基因组上病毒基因表达和表观遗传标记的程度，我们检查了VZV感染的分化神经元，在培养中保持长达3周的培养，而没有细胞病变。用干扰素治疗这些神经元显着降低了病毒基因表达。这是我们假设治疗以限制VZV基因表达的神经元将产生一个模型系统，该模型系统概括了潜在感染的人神经节神经元中的VZV转录。为了检验我们的假设，我们将：通过抗病毒剂和由先天性和适应性免疫系统细胞产生的抗病毒剂和分子在体外处理VZV非散型神经元，并通过RT-PCR检查VZV基因表达（AIM 1）；确定用acyclovir和多个细胞因子治疗后，在非散膜感染神经元内的VZV基因表达和表观遗传标记的VZV DNA的物理状态（AIM 2）。在体外开发VZV潜伏期的模型将允许研究通常需要获取数千个人为神经节。深入了解VZV如何长期存在于潜在感染的人类神经细胞中是制定策略的前提，以防止导致病毒重新激活的事件级联，这是严重的神经系统疾病和失明的原因，尤其是在迅速增加的古老和不受欢迎的人群中。