A major contributor of serious multisystem disease in the elderly: varicella zoster virus-induced inflammation

本项目的目标是预防老年人水痘带状疱疹复发后的疾病 病毒（VZV），与衰老相关的疾病的最常见的病毒学原因。到2050年，超过8300万人 美国人将超过65岁，95%的人携带潜伏的VZV。随着免疫系统的老化，VZV将 在>50%的情况下重新激活，产生带状疱疹（带状疱疹），并发带状疱疹后神经痛，以及严重的 多系统疾病伴或不伴皮疹，包括痴呆、中风、巨细胞动脉炎、视力丧失、烧灼感 口腔综合征、心肌梗死和肠和膀胱功能障碍。虽然带状疱疹疫苗减少了 虽然它在带状疱疹和PHN的发病率方面没有明显作用，但在其他VZV相关疾病中没有显示出保护作用。的 这些疾病的特征性主题是持续的VZV诱导的炎症，导致组织 损害因此，本计划项目由3个项目和2个核心（行政和科学）组成，将： 确定VZV在以巨细胞动脉炎为特征的持续性血管炎症中的作用 (GCA)是中老年人最常见的全身性血管炎，可导致头痛、中风和失明; 检查GCA中血管外膜成纤维细胞的表观遗传变化， 促炎表型;并跟踪病毒感染和炎症的演变， 水痘病毒再活化猴模型中带状疱疹后6个月的临床相关组织。 项目1将确定促炎环境，并确定福尔马林固定的石蜡中的生物标志物， 使用一种新的、经验证的RNA测序， 该策略提供完整的细胞和病毒转录组表达谱。该项目还将 测定从活检时立即获得的GCA阳性TA分离的T细胞的VZV抗原特异性。 项目2检验了从GCA阳性TA中分离的外膜成纤维细胞经历表观遗传的假设， 重新编程，使它们具有促炎性，提高了用组蛋白去乙酰化酶治疗的可能性 抑制剂的项目3使用灵长类动物模型来确定关键的病毒-宿主免疫细胞相互作用， 带状疱疹后多个时间的多个组织，否则不可能在人体中进行研究 因为在带状疱疹后的规定时间VZV感染的组织不可用。该项目的成功是 通过以下方式确保：1）临床医生和具有VZV生物学，免疫学， 表观遗传学、生物信息学、生物统计学和眼科学; 2）事先制定拟议方案;以及 3)从落基山脉地区的多家医院/诊所获得新鲜的TA活检， 灵长类动物组织通过与杜兰国家灵长类动物研究中心合作。总之，这些研究 具有很大的转化前景，因为它们将提供有关导致 持续的VZV诱导的炎症和组织损伤，从而提供新的治疗靶点， 减少/预防主要影响脆弱老龄人口的临床疾病。

The goal of this Program Project is to prevent disease in the elderly upon reactivation of varicella zoster virus (VZV), the most common virological cause of disease associated with aging. By 2050, >83 million Americans will be over 65 years old with 95% harboring latent VZV. As the immune system ages, VZV will reactivate in >50% to produce zoster (shingles) complicated by postherpetic neuralgia, as well as serious multisystem disorders with or without rash including dementia, stroke, giant cell arteritis, vision loss, burning mouth syndrome, myocardial infarction, and bowel and bladder dysfunction. While zoster vaccine reduces the incidence of zoster and PHN, it has not been shown to be protective in other VZV-associated diseases. The characteristic theme in these diseases is persistent, VZV-induced inflammation that results in tissue damage. Thus, this Program Project, composed of 3 Projects and 2 Cores (Administrative and Scientific) will: determine the role of VZV in persistent vascular inflammation that characterizes giant cell arteritis (GCA), the most common systemic vasculitis in elderly that causes headaches, stroke and blindness; examine epigenetic changes in vascular adventitial fibroblasts in GCA that contribute to a persistent proinflammatory phenotype; and trace the evolution of virus infection and inflammation in multiple clinically relevant tissues up to 6 months post-zoster in a simian model of varicella virus reactivation. Project 1 will determine the proinflammatory environment and identify biomarkers in formalin-fixed, paraffin- embedded temporal arteries from GCA patients (GCA-positive TAs) using a novel, validated RNA sequencing strategy that provides complete cellular and viral transcriptome expression profiles. This Project will also determine VZV antigen specificity of T cells isolated from GCA-positive TAs acquired immediately at biopsy. Project 2 tests the hypothesis that adventitial fibroblasts isolated from GCA-positive TAs undergo epigenetic reprogramming such that they are proinflammatory, raising the possibility of treatment with histone deacetylase inhibitors. Project 3 uses a primate model to determine critical virus-host immune cell interactions within multiple tissues at multiple times post-zoster, a study which is otherwise impossible to conduct in humans since VZV-infected tissue at defined times post-zoster is not available. The success of this Program Project is ensured by: 1) collaborations among clinicians and scientists with expertise in VZV biology, immunology, epigenetics, bioinformatics, biostatistics and ophthalmology; 2) prior establishment of proposed protocols; and 3) availability of fresh TA biopsies from multiple hospitals/clinics in the Rocky Mountain Region and access to primate tissues through collaborations with Tulane National Primate Research Center. Together, the studies hold great translational promise since they will provide valuable information about the mechanisms leading to persistent VZV-induced inflammation and tissue damage, thereby providing new therapeutic targets to reduce/prevent clinical disease predominantly affecting the vulnerable aging population.