Mechanisms of varicella virus-induced multisystem disease using a primate model

使用灵长类动物模型研究水痘病毒诱导的多系统疾病的机制

• 批准号: 10343677
• 负责人: RAVI MAHALINGAM
• 金额: $ 92.85万
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10343677
• 关键词: Adrenal Glands; Affect; Age-Years; American; Animals; Apoptosis; Arteries; Autoimmune Diseases; Biological Assay; Biopsy; Blindness; Blood; Blood Vessels; Bronchoalveolar Lavage; Burning Mouth Syndrome; CXCL10 gene; Cells; Cellular Assay; Chickenpox; Chronic; Clinical; Cost of Illness; Dendritic Cells; Detection; Development; Disease; Down-Regulation; Elderly; Enzyme-Linked Immunosorbent Assay; Esophagitis; Exanthema; Fibroblasts; Flow Cytometry; Frequencies; Ganglia; Gastroparesis; Genetic Transcription; Health Care Costs; Herpes zoster disease; Herpesvirus Type 3; Human; IL8 gene; Immune; Immune response; Immunocompromised Host; Immunofluorescence Immunologic; Immunosuppression; In Vitro; Inflammation; Inflammatory; Interleukin-6; Intervention; Intestines; Lung; Lymphadenitis; Macaca; Macaca mulatta; Major Histocompatibility Complex; Matrix Metalloproteinases; Modeling; Monkeys; Multi-Infarct Dementia; Organ; Pain; Pathologic; Pathway interactions; Patients; Phenotype; Play; Population; Postherpetic neuralgia; Primary Infection; Primates; Production; Protocols documentation; Pulmonary Inflammation; Quality of life; RNA; Rhesus; Role; Sampling; Skin; Stains; Stroke; Suicide; T-Cell Activation; T-Lymphocyte; Tacrolimus; Techniques; Temporal Arteritis; Testing; Time; Tissues; Tumor-infiltrating immune cells; Vasculitis; Viral; Viral Antigens; Viremia; Virus; Virus Diseases; Virus Replication; base; body system; burden of illness; cerebral artery; clinically relevant; cytokine; immune activation; immune function; inflammatory marker; insight; lymph nodes; macrophage; monocyte; neutrophil; nonhuman primate; novel; prevent; programmed cell death ligand 1; receptor; transcriptome; transcriptome sequencing; varicella zoster virus vasculopathy

By 2050, the number of Americans 65 years and older is projected to be 83.7 million, and the burden of diseases and healthcare costs will be staggering. An important cause of multi-system disease in the elderly is varicella zoster virus (VZV) reactivation. More than 95% of humans harbor latent VZV in their ganglia following primary infection (varicella, chickenpox) and 50% of them will reactivate VZV by 85 years of age. Serious complications of VZV reactivation include postherpetic neuralgia (PHN), giant cell arteritis, burning mouth syndrome, stroke, multi-infarct dementia, blindness, esophagitis, pneumonitis, and gastroparesis. Thus, VZV reactivation affects multiple organs. VZV-induced persistent inflammation has emerged as an important pathologic contributor in most of these disorders. The mechanism(s) by which inflammatory cells persist in infected tissue is unknown; however human vascular cells infected in vitro with VZV show downregulated expression of programmed death ligand 1 (PD-L1) and major histocompatibility complex 1. Decreased PD-L1 expression contributes to persistent inflammation in autoimmune diseases, raising the possibility that VZV- induced downregulation of PD-L1 also contributes to persistent inflammation. Since VZV is an exclusively human virus, we will investigate the role of virus-induced PD-L1 dysregulation across multiple, clinically relevant tissues in non-human primates infected with simian varicella virus (SVV), a model that we developed in the last two decades. SVV, the primate counterpart of VZV, causes varicella on primary infection, establishes latency in ganglia, and reactivates later to produce zoster and multi-system disease. Preliminary results reveal SVV antigen- and CXCL10-induced T cell infiltration in ganglia 4 months after tacrolimus- induced SVV reactivation in rhesus macaques, similar to the chronic ganglionitis seen in PHN patients. Like VZV, SVV infection of rhesus fibroblasts in culture leads to decreased PD-L1 expression. Thus, we hypothesize that after SVV reactivation, viral antigen and activated immune cells persist in multiple tissues for months, in part due to dysregulation of PD-L1, thereby contributing to clinical disease seen in inflamed tissue in the elderly. To test our hypothesis, we will analyze the extent of SVV infection and associated inflammation in multiple tissues longitudinally after zoster (Aim 1). We will also correlate the composition, activation state and function of immune cells in multiple tissues longitudinally after zoster with the presence of SVV and inflammation (Aim 2). Overall, these studies in the non-human primate model of VZV reactivation will provide insight into multiple virus-infected tissues, not available in humans, to elucidate the mechanisms of viral persistence and inflammation, information that will be translatable to development of new intervention strategies to inhibit multi-system disease caused by VZV in elderly humans.

到2050年，65岁及以上的美国人口预计将达到8370万，而 疾病和医疗成本将是惊人的。老年人多系统疾病的一个重要原因是 水痘带状疱疹病毒(VZV)重新激活。超过95%的人在以下神经节中存在潜伏的VZV 原发感染(水痘、水痘)，其中50%的人会在85岁前重新激活VZV。严重的 VZV重新激活的并发症包括带状疱疹后神经痛(PHN)、巨细胞动脉炎、口腔灼热 综合症、中风、多发性梗死性痴呆、失明、食管炎、肺炎和胃瘫。因此，VZV 重新激活会影响多个器官。VZV诱导的持续性炎症已成为一种重要的 这些疾病中的大多数是病理因素造成的。炎症细胞持续存在的机制(S) 感染组织尚不清楚，但体外感染VZV的人血管细胞表达下调 程序性死亡配体1(PD-L1)和主要组织相容性复合体1的表达：PD-L1减少 表达有助于自身免疫性疾病的持续性炎症，增加了VZV- PD-L1的诱导下调也是持续性炎症的原因之一。由于VZV是一家独家 人类病毒，我们将研究病毒诱导的PD-L1失调在多个临床上的作用 我们建立的猴水痘病毒(SVV)感染非人类灵长类动物的相关组织 在过去的二十年里。SVV是VZV的灵长类病毒，在初次感染时会引起水痘， 在神经节中建立潜伏期，然后重新激活，产生带状疱疹和多系统疾病。初步 结果显示，在他克莫司治疗4个月后，SVV抗原和CXCL10诱导的T细胞在神经节内浸润。 在恒河猴中诱导SVV重新激活，类似于PHN患者的慢性神经节炎。喜欢 VZV、SVV感染恒河猴成纤维细胞可导致PD-L1表达下降。因此，我们 假设在SVV重新激活后，病毒抗原和激活的免疫细胞持续存在于 组织长达数月，部分原因是PD-L1调节失调，从而导致临床疾病 在老年人发炎的组织中。为了验证我们的假设，我们将分析SVV感染的程度和 带状疱疹后多个组织纵向相关炎症(目标1)。我们还将关联 纵向带状疱疹后多个组织免疫细胞的组成、激活状态和功能 存在SVV和炎症(目标2)。总体而言，这些研究是在VZV的非人灵长类模型中进行的 重新激活将提供对多个感染病毒的组织的洞察，这些组织在人类中不可用，以阐明 病毒持续和炎症的机制，可翻译为新的发展的信息 抑制VZV在老年人中引起的多系统疾病的干预策略。