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（包括动脉粥样硬化和血管炎）的发病机制具有广泛意义。虽然许多血管炎的病因尚不清楚，但有流行病学证据表明某些血管炎的感染性病因，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γ-疱疹病毒-68（YHV-68）的持续复制导致小鼠大血管中的血管病理学，其与人类川崎和高安动脉炎相似。细胞因子干扰素γ（IFN γ）防止YHV-68的再活化从潜伏期并保护宿主免于血管病理。YHV-68中的病毒基因，开放阅读框50（ORF 50），对于诱导裂解再活化是必要的且足够的，并且IFN γ抑制ORF 50转录和启动子活性，表明IFN γ信号传导途径可以直接靶向ORF 50启动子。中心假设是IFN γ通过作用于病毒ORF 50启动子中的特定元件来抑制YHV-68病毒从潜伏期再活化，从而保护免受病毒复制诱导的血管炎。该假设将通过以下方式进行测试：（1）通过对ORF 50启动子内的元件进行突变分析来鉴定该启动子中的顺式作用IFN γ应答元件;（2）通过用ORF 50启动子中的病毒突变体感染小鼠来阐明ORF 50启动子中的IFN γ应答元件在建立潜伏期和从潜伏期再激活中的作用，以及对潜伏期建立和再激活的离体分析;（3）通过用病毒突变体感染小鼠和动脉炎严重程度的组织学评分来评估ORF 50启动子元件在YHV-68诱导的大血管炎中的作用。该项目可能为IFN γ应答元件在潜伏期和再激活中的作用以及病毒和宿主因子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，如动脉粥样硬化和血管炎，并且可能是致命的。了解免疫系统和病毒在造成血管损伤中的作用可能会提供新的治疗靶点，并对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.