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

基本信息

  • 批准号:
    10097969
  • 负责人:
  • 金额:
    $ 101.2万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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岁及以上的美国人预计将达到8370万, 疾病和医疗费用将会惊人。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)再激活。超过95%的人在他们的神经节中潜伏VZV, 原发性感染(水痘,水痘)和50%的人将重新激活VZV的85岁。严重 VZV再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 综合征、中风、多梗塞性痴呆、失明、食管炎、肺炎和胃轻瘫。因此,VZV 再激活会影响多个器官。VZV诱导的持续性炎症已经成为一种重要的 在大多数这些疾病的病理贡献者。炎症细胞持续存在的机制 感染的组织是未知的;然而,在体外用VZV感染的人血管细胞显示下调 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降低 表达有助于自身免疫性疾病的持续炎症,提高了VZV- 诱导的PD-L1下调也有助于持续性炎症。由于VZV是一个专门的 人类病毒,我们将研究病毒诱导的PD-L1失调在多个临床 在非人灵长类动物感染猴水痘病毒(SVV),我们开发的模型, 在过去的二十年里。SVV是VZV的灵长类对应物,在初次感染时引起水痘, 在神经节中建立潜伏期,并且稍后再激活以产生带状疱疹和多系统疾病。初步 结果显示,他克莫司治疗后4个月,SVV抗原和CXCL 10诱导的T细胞在神经节浸润, 在恒河猴中诱导SVV再激活,类似于PHN患者中观察到的慢性神经节炎。像 VZV、SVV感染培养的恒河猴成纤维细胞导致PD-L1表达降低。因此我们 假设在SVV再活化后,病毒抗原和活化的免疫细胞在多个细胞中持续存在, 组织数月,部分原因是PD-L1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, 带状疱疹后多个组织纵向相关炎症(目的1)。我们还将关联 带状疱疹后纵向多组织免疫细胞的组成、活化状态和功能 SVV和炎症的存在(目的2)。总体而言,这些研究在非人灵长类动物模型的VZV 重新激活将提供深入了解多种病毒感染的组织,在人类中不可用,以阐明 病毒持久性和炎症的机制,信息将被翻译为新的发展, 干预策略,以抑制VZV引起的老年人多系统疾病。

项目成果

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RAVI MAHALINGAM其他文献

RAVI MAHALINGAM的其他文献

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{{ truncateString('RAVI MAHALINGAM', 18)}}的其他基金

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:
    9491549
  • 财政年份:
    2009
  • 资助金额:
    $ 101.2万
  • 项目类别:
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:
    10542748
  • 财政年份:
    2009
  • 资助金额:
    $ 101.2万
  • 项目类别:
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
  • 财政年份:
    2009
  • 资助金额:
    $ 101.2万
  • 项目类别:
VARICELLA VIRUS LATENCY
水痘病毒潜伏期
  • 批准号:
    6565245
  • 财政年份:
    2001
  • 资助金额:
    $ 101.2万
  • 项目类别:
VARICELLA VIRUS LATENCY
水痘病毒潜伏期
  • 批准号:
    6410648
  • 财政年份:
    2000
  • 资助金额:
    $ 101.2万
  • 项目类别:
VARICELLA VIRUS LATENCY
水痘病毒潜伏期
  • 批准号:
    6302839
  • 财政年份:
    1999
  • 资助金额:
    $ 101.2万
  • 项目类别:
VARICELLA VIRUS LATENCY
水痘病毒潜伏期
  • 批准号:
    6346296
  • 财政年份:
    1999
  • 资助金额:
    $ 101.2万
  • 项目类别:
VARICELLA VIRUS LATENCY
水痘病毒潜伏期
  • 批准号:
    6112505
  • 财政年份:
    1998
  • 资助金额:
    $ 101.2万
  • 项目类别:
IMMUNOBIOLOGY OF VARICELLA AND ZOSTER IN A PRIMATE MODEL
灵长类动物模型中水痘和带状疱疹的免疫生物学
  • 批准号:
    8636736
  • 财政年份:
  • 资助金额:
    $ 101.2万
  • 项目类别:
IMMUNOBIOLOGY OF VARICELLA AND ZOSTER IN A PRIMATE MODEL
灵长类动物模型中水痘和带状疱疹的免疫生物学
  • 批准号:
    7578632
  • 财政年份:
  • 资助金额:
    $ 101.2万
  • 项目类别:

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