A study of the molecular pathogenesis of Murray Valley encephalitis virus in mice using infectious clone-derived virus

使用传染性克隆衍生病毒研究小鼠墨累谷脑炎病毒的分子发病机制

• 批准号: nhmrc : 110200
• 负责人: Prof Peter Mcminn
• 金额: $ 12.98万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2000
• 资助国家: 澳大利亚
• 起止时间: 2000-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/study-molecular-pathogenesis-derived-virus/76072
• 关键词: study; molecular; pathogenesis; Murray; Valley

The significance of this project derives primarily from the public health problem posed by epidemics of Murray Valley encephalitis in Australia and, more importantly, by the very much larger and more frequent epidemics of Japanese encephalitis in southeast Asia. Reported case fatality rates of Murray Valley encephalitis and of Japanese encephalitis range from 20 to 40%. Rates of neurological sequelae (motor deficits, mental retardation, convulsions, memory loss) are high among survivors and impose a considerable burden on affected individuals and on community health and rehabilitation services. Currently there are no effective treatments, other than supportive measures, available for acute flavivirus encephalitis. The research outlined in this grant application is designed to understand the complex interaction between a pathogenic virus and it's mammalian host at the molecular, cellular and whole animal level. To achieve this aim, we have developed an infectious cDNA clone of Murray Valley encephalitis virus, allowing us to create genetically defined attenuated viruses containing single or limited amino acid differences from the virulent wild-type virus. This research will allow us to achieve a comprehensive understanding of how single or limited nucleotide changes in the genomes of laboratory-derived mutants result in attenuation of virulence in a mammalian host . This research has important implications for the development of genetically defined, live-attenuated flavivirus vaccines engineered from infectious cDNA clones. We have recently shown that the pathogenesis of Murray Valley encephalitis in mice results, in part, from host inflammatory responses. Thus, we plan to rigorously analyze the inflammatory responses to MVE infection in mice and to assess the ability of several anti-inflammatory agents to alleviate the clinical manifestations of acute Murray Valley encephalitis or it's neurological sequelae in mice.

该项目的重要性主要源于澳大利亚墨累谷脑炎流行所造成的公共卫生问题，更重要的是，东南亚更大规模、更频繁的日本脑炎流行所带来的公共卫生问题。墨累谷脑炎和日本脑炎报告的病死率在 20% 至 40% 之间。幸存者中神经系统后遗症（运动缺陷、智力迟钝、抽搐、记忆丧失）的发生率很高，给受影响的个人以及社区卫生和康复服务带来了相当大的负担。目前，除了支持性措施外，尚无针对急性黄病毒脑炎的有效治疗方法。本拨款申请中概述的研究旨在在分子、细胞和整个动物水平上了解病原病毒与其哺乳动物宿主之间的复杂相互作用。为了实现这一目标，我们开发了墨累谷脑炎病毒的传染性 cDNA 克隆，使我们能够创建基因定义的减毒病毒，其中包含与强毒野生型病毒的单一或有限氨基酸差异。这项研究将使我们能够全面了解实验室衍生突变体基因组中的单个或有限核苷酸变化如何导致哺乳动物宿主毒力减弱。这项研究对于开发由传染性 cDNA 克隆设计的基因定义的减毒活黄病毒疫苗具有重要意义。我们最近表明，小鼠墨累谷脑炎的发病机制部分是由宿主炎症反应引起的。因此，我们计划严格分析小鼠对 MVE 感染的炎症反应，并评估几种抗炎药物缓解小鼠急性墨累谷脑炎或其神经后遗症临床表现的能力。