Animal models of hantavirus cardiopulmonary disease

描述(申请人提供)：汉坦病毒心肺综合征(HCPS)是一种经常致命的人畜共患病，在美洲流行。引起HCPS的安第斯病毒(ANDV)和其他汉坦病毒是NIAID优先病原体(C类)。需要建立HCPS的实验室模型来阐明HCPS的发病机制，并严格评估该疾病的候选治疗方法的疗效。这项应用的广泛目标是扩展和完善我们对汉坦病毒感染在啮齿动物模型中的发病机制的认识。这项应用的第一个目的是表征ANDV在仓鼠中的感染过程(特别是在致死结果之前或同时发生的病理生理事件)，评估ANDV感染对仓鼠心脏的影响，并确定ANDV在仓鼠中是否实质上比马普拉病毒更致命。在未来的研究中，这两种病毒之间的致命性显著差异将被用来阐明在人类疾病的仓鼠模型中，汉坦病毒感染的毒力决定因素。第二个目的是评估诱导型一氧化氮合酶在实验室小鼠HCPS样病发病机制中的作用。初步研究结果表明，感染的肺和心脏组织中强烈的氧化反应是对实验室小鼠HCPS样疾病进展的关键威慑。将进行一系列研究，以测试ANDV和MAPV在诱导型一氧化氮合酶缺陷基因敲除小鼠中的致病性和毒力。一种严重或致命性HCPS的小鼠模型可以实质性地加强对导致危及生命的肺水肿的毛细血管渗漏的发病机制的研究。

DESCRIPTION (provided by applicant): Hantavirus cardiopulmonary syndrome (HCPS) is a frequently fatal zoonosis that is endemic in the Americas. Andes virus (ANDV) and other Hantaviruses that cause HCPS are NIAID Priority Pathogens (Category C). Laboratory models of HCPS are needed to elucidate the pathogenesis of HCPS and to rigorously assess the efficacy of candidate therapies for the disease. The broad objective of this application is to extend and refine our knowledge of the pathogenesis of hantaviral infections in rodent models of HCPS. The first aim of this application is to characterize the course of ANDV infection in the hamster (particularly the pathophysiological events that precede or coincide with lethal outcome), assess the effect of ANDV infection in the hamster heart, and determine whether ANDV is substantively more lethal than Maporal virus in the hamster. A substantial difference in lethality between the viruses will be used in future studies to elucidate the viral determinants of the virulence of hantaviral infections in hamster models of human disease. The second aim is to assess the role of inducible nitric oxide synthase in the pathogenesis of HCPS-like disease in the laboratory mouse. The results of a preliminary study suggest that the vigorous oxidative response in infected lung and heart tissues is a critical deterrent to the progression of HCPS-like disease in laboratory mice. A series of studies will be done to test the pathogenicity and virulence of ANDV and MAPV each in knockout mice deficient in inducible nitric oxide synthase. A mouse model of severe or lethal HCPS could substantively augment studies on the pathogenesis of the capillary leak that results in the life-threatening pulmonary edema HCPS.