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

该计划项目的目标是预防老年人在水痘带状疱疹重新激活后的疾病 病毒(VZV)，与衰老有关的疾病的最常见病毒学原因。到2050年，&gt；8300万 美国人将超过65岁，95%的人患有潜伏性VZV。随着免疫系统的老化，VZV将 重新激活50%以产生带状疱疹(带状疱疹)并伴有带状疱疹后神经痛，以及严重的 有或没有皮疹的多系统疾病，包括痴呆、中风、巨细胞动脉炎、视力丧失、灼热 口腔综合征，心肌梗死，以及肠和膀胱功能障碍。虽然带状疱疹疫苗可以减少 除了带状疱疹和PHN的发病率，它还没有被证明对其他与VZV相关的疾病具有保护作用。这个 这些疾病的特征是由VZV引起的持续性炎症，导致组织 损坏。因此，该方案项目由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)，老年人最常见的系统性脉管炎，会导致头痛、中风和失明； 检查GCA中血管外膜成纤维细胞的表观遗传学变化 炎性前表型；并追踪病毒感染和炎症的演变 在水痘病毒重新激活的猿猴模型中，带状疱疹后6个月的临床相关组织。 项目1将确定致炎环境，并确定福尔马林固定、石蜡- 应用一种新的、有效的RNA测序技术对GCA患者(GCA阳性TA)的颞动脉进行包埋 提供完整的细胞和病毒转录组表达谱的策略。该项目还将 从活检时立即获得的GCA阳性肿瘤组织中分离出T细胞，以确定VZV抗原的特异性。 项目2测试了从GCA阳性的TA中分离的外膜成纤维细胞经历表观遗传学的假设 重新编程，使它们成为促炎性细胞，增加了用组蛋白脱乙酰酶治疗的可能性 抑制剂。项目3使用灵长类模型来确定关键的病毒-宿主免疫细胞相互作用 带状疱疹后多次出现多个组织，这是一项在人类身上不可能进行的研究 由于在规定时间感染带状疱疹病毒的组织无法获得带状疱疹后。该计划项目的成功之处在于 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)事先建立拟议的方案；以及 3)可从落基山地区的多家医院/诊所获得新鲜的TA活检，并可获得 灵长类组织通过与杜兰国家灵长类研究中心的合作。总之，这些研究 拥有巨大的翻译前景，因为它们将提供有关导致 持续的VZV引起的炎症和组织损伤，从而提供新的治疗靶点 减少/预防主要影响脆弱老龄化人口的临床疾病。

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.