MECHANISMS OF VIRUS-INDUCED ELASTIC ARTERITIS

病毒引起的弹力动脉炎的机制

• 批准号: 6330162
• 负责人: HERBERT W VIRGIN
• 金额: $ 31.72万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-15 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6330162
• 关键词: MECHANISMS; VIRUS; INDUCED; ELASTIC; ARTERITIS

We have developed a novel small animal model of virus induced elastic arteritis that will allow us to define fundamental mechanisms of vascular injury and the role of virus infection and the immune system in controlling or promoting chronic vascular pathology [Nature Medicine, 1997, 3(12):1346-1353]. Little is known about mechanisms that initiate inflammatory lesions of large elastic arteries, and the mechanisms underlying vasculitis are incompletely defined. Recently, attention has been paid to herpesviruses and activated lymphocytes as possible causes or cofactors in vascular injury. Mechanistic studies in a tractable model system have not been performed to determine how herpesvirus infection and the immune system interact to generate or control vascular pathology. We discovered that a newly characterized murine gamma-herpesvirus (gammaHV68) causes striking elastic arteritis in normal mice, and that interferon-gamma (IFNgamma) unresponsive mice and B cell deficient mice are much more susceptible than normal mice to induction of arteritis by gammaHV68. Further analysis revealed (i) a novel tropism of gammaHV68 for vascular smooth muscle cells, (ii) that productive replication is occurring in arteritic lesions, (iii) that IFNgamma acts primarily at the level of somatic cells, and (iv) the pathology of arteritic lesions in IFN-unresponsive and B cell deficient mice are strikingly different. To provide molecular tools for analysis of viral contributions to chronic arteritis we sequenced the genome of gammaHV68 (119,450 bp), demonstrating that gammaHV68 is closely related to the human gamma- herpesviruses Epstein-Barr virus and Kaposi's sarcoma herpesvirus. We have recently isolated mutant and marker rescue gammaHV68, and identified candidate latency-associated gammaHV68 genes. The availability of genetic tools for analysis of the host immune response arid the role of specific viral genes, will allow us to define mechanisms of gammaHV68 induced arteritis as follows. Aim 1. Determine the contribution of latent and productive gammaHV68 infection to chronic arteritis. Aim 2. Determine the mechanism by which IFNgamma regulates arteritis. Aim 3. Determine the mechanism by which B cells regulate arteritis.

我们已经开发了一种新的病毒诱导的弹性动脉炎的小动物模型，这将使我们能够确定血管损伤的基本机制以及病毒感染和免疫系统在控制或促进慢性血管病理中的作用[Nature Medicine，1997，3（12）：1346-1353]。 目前对大弹性动脉炎性病变的发生机制知之甚少，血管炎的发病机制也不完全清楚。 近年来，疱疹病毒和活化的淋巴细胞作为血管损伤的可能原因或辅助因素受到关注。 尚未在易处理的模型系统中进行机制研究以确定疱疹病毒感染和免疫系统如何相互作用以产生或控制血管病变。 我们发现一种新的鼠γ-疱疹病毒（gammaHV 68）在正常小鼠中引起显著的弹性动脉炎，并且γ-干扰素（IFN-γ）无反应小鼠和B细胞缺陷小鼠比正常小鼠更容易受到γ-疱疹病毒68诱导的动脉炎的影响。 进一步的分析揭示了（i）γ HV 68对血管平滑肌细胞的新向性，（ii）在动脉炎病变中发生了生产性复制，（iii）IFN γ主要在体细胞水平起作用，和（iv）IFN无应答小鼠和B细胞缺陷小鼠中动脉炎病变的病理学显著不同。 为了提供用于分析病毒对慢性动脉炎的贡献的分子工具，我们对γ HV 68的基因组（119，450 bp）进行测序，证明γ HV 68与人γ疱疹病毒Epstein-Barr病毒和卡波西肉瘤疱疹病毒密切相关。 我们最近已经分离出突变体和标志物拯救gammaHV 68，并确定了候选的潜伏期相关的gammaHV 68基因。 用于分析宿主免疫应答和特定病毒基因的作用的遗传工具的可用性将使我们能够如下定义γ HV 68诱导的动脉炎的机制。 目标1。确定潜伏性和生产性γ HV 68感染对慢性动脉炎的影响。 目标2.确定IFN γ调节动脉炎的机制。目标3.确定B细胞调节动脉炎的机制。