Animal models of hantavirus cardiopulmonary disease

描述（由申请人提供）：汉坦病毒心肺综合征（HCPS）是一种常见的致命人畜共患病，在美洲流行。安第斯病毒（ANDV）和其他引起HCPS的汉坦病毒是NIAID优先病原体（C类）。需要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。该应用程序的广泛目标是扩展和完善我们对HCPS啮齿动物模型中汉坦病毒感染发病机制的了解。本应用程序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在仓鼠心脏中的感染效果，并确定ANDV在仓鼠中是否比Maporal病毒更致命。在未来的研究中，这两种病毒在致死性上的巨大差异将用于阐明汉坦病毒感染在人类疾病仓鼠模型中的毒力的病毒决定因素。第二个目的是评估诱导型一氧化氮合酶在实验室小鼠hcps样疾病发病机制中的作用。一项初步研究的结果表明，在实验室小鼠中，受感染的肺和心脏组织中强烈的氧化反应是阻止hcps样疾病进展的关键因素。在诱导型一氧化氮合酶缺乏的敲除小鼠中，将进行一系列的研究来测试ANDV和MAPV各自的致病性和毒力。严重或致死性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HCPS的毛细血管泄漏发病机制的研究。

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.