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自澳大利亚默里山谷脑炎的流行，更重要的是，东南亚日本脑炎的流行病所带来的公共卫生问题。报告的默里河谷脑炎和日本脑炎的病例死亡率范围为20％至40％。幸存者的神经后遗症（运动缺陷，智力低下，抽搐，记忆力丧失）的率很高，并给受影响的个体以及社区健康和康复服务带来了相当大的负担。目前，除了提供支持措施以外，还没有有效的治疗方法，可用于急性黄素脑炎。该赠款应用中概述的研究旨在了解病原病毒与它是分子，细胞和整个动物水平的哺乳动物宿主之间的复杂相互作用。为了实现这一目标，我们开发了默里山谷脑炎病毒的传染性cDNA克隆，使我们能够创建含有毒性野生型病毒的单个或有限氨基酸差异的遗传定义的减毒病毒。这项研究将使我们能够对实验室衍生突变体基因组中的单个或有限核苷酸的变化进行全面了解，从而导致哺乳动物宿主的毒力衰减。这项研究对从传染性cDNA克隆设计的遗传定义，活衰减的黄病毒疫苗的发展具有重要意义。我们最近表明，小鼠穆雷山谷脑炎的发病机理部分来自宿主炎症反应。因此，我们计划严格分析小鼠中MVE感染的炎症反应，并评估几种抗炎剂减轻急性Murray山谷脑炎的临床表现或小鼠神经系统的临床表现的能力。