Role of Interferon-gamma in Viral Reactivation and Vasculitis

Washington University, Saint Louis MO

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Abstract

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.