Role of Interferon-gamma in Viral Reactivation and Vasculitis

描述(由申请人提供)：研究血管壁炎症的基本机制可能对理解心血管疾病的发病机制有广泛的意义，包括动脉粥样硬化和血管炎。虽然许多脉管炎的病因尚不清楚，但有流行病学证据表明，其中一些是感染性病因学，包括川崎病，这是发达国家儿童获得性心脏病的最常见原因。小动物模型使研究人员能够研究宿主和病原体中导致血管损伤的因素，并可能导致新的治疗靶点。先前的研究已经证明，小鼠伽玛-疱疹病毒68(YHV-68)的持续复制会导致小鼠大血管中的血管病理，类似于人类川崎病和高屋松氏动脉炎。细胞因子干扰素-γ(IFNy)可防止YHV-68潜伏期重新激活，并保护宿主免受血管病变的影响。YHV-68的病毒基因开放阅读框50(ORF50)是诱导裂解再激活的必要条件和充分条件，而IFNy抑制ORF50转录和启动子活性，提示IFNy信号通路可能直接针对ORF50启动子。中心假设是，IFNy通过作用于病毒ORF50启动子中的特定元件，抑制YHV-68病毒的潜伏期重新激活，从而预防病毒复制诱导的脉管炎。将通过以下步骤检验这一假说：(1)通过对ORF50启动子内元件的突变分析确定ORF50启动子中的顺式作用IFNy反应元件；(2)阐明ORF50启动子中的IFNy响应元件在感染ORF50启动子中的病毒突变的小鼠建立潜伏期和潜伏期重新激活中的作用，并对潜伏期的建立和重新激活进行体外分析；(3)通过感染病毒突变体和动脉炎严重程度的组织学评分来评估ORF50启动子元件在YHV-68诱导的大血管炎中的作用。这一项目可能会对IFNy反应元件在潜伏期和重新激活中的作用，以及病毒和宿主因素在病毒诱导的血管炎的建立和严重程度中的作用提供新的见解。相关性：血管炎症与严重的长期心血管问题有关，如动脉粥样硬化和脉管炎，可能是致命的。了解免疫系统和病毒在造成血管损伤中所起的作用，可能会为治疗提供新的靶点，并为血管损伤的根本原因提供新的见解。

DESCRIPTION (provided by applicant): Studying the fundamental mechanisms involved in inflammation of the blood vessel wall may have broad implications for understanding the pathogenesis of cardiovascular diseases, including atherosclerosis and vasculitis. While the etiologies of many vasculitides are unknown, there is epidemiologic evidence for an infectious etiology for some, including Kawasaki's disease, which is the most common cause of acquired heart disease in children in developed countries. Small animal models enable investigators to study the factors in the host and pathogen that contribute to vascular damage and may lead to novel therapeutic targets. Previous research has demonstrated that persistent replication of the murine gamma-herpesvirus- 68 (YHV-68) leads to vascular pathology in the great vessels of mice bearing resemblance to human Kawasaki's disease and Takayasu's arteritis. The cytokine, interferon gamma (IFNy), prevents reactivation of YHV-68 from latency and protects the host from vascular pathology. A viral gene in YHV-68, open reading frame 50 (ORF50), is both necessary and sufficient to induce lytic reactivation and IFNy suppresses ORF50 transcription and promoter activity, suggesting that IFNy signaling pathways may target the ORF50 promoter directly. The central hypothesis is that IFNy suppresses YHV-68 viral reactivation from latency by acting on specific elements in the viral ORF50 promoter, thereby protecting against viral replication-induced vasculitis. This hypothesis will be tested by (1) identifying the cis-acting IFNy responsive elements in the ORF50 promoter by mutational analysis of elements within this promoter; (2) elucidating the role of IFNy responsive elements in the ORF50 promoter in the establishment of latency and reactivation from latency by infection of mice with viral mutants in the ORF50 promoter and ex vivo analysis of latency establishment and reactivation; and (3) evaluating the role of ORF50 promoter elements in YHV-68-induced large vessel vasculitis by infecting mice with viral mutants and histologic scoring of arteritis severity. This project may provide new insights into the role of IFNy responsive elements in latency and reactivation and the role of virus and host factors in the establishment and severity of virus-induced vasculitis. Relevance: Inflammation of blood vessels is associated with serious long-term cardiovascular problems, such as atherosclerosis and vascultis, and can be fatal. Understanding the roles that the immune system and viruses play in causing damage to blood vessels may provide novel therapeutic targets and new insights into the underlying causes of vascular damage.