Animal models of hantavirus cardiopulmonary disease

汉坦病毒心肺疾病动物模型

• 批准号: 6856895
• 负责人: CHARLES F FULHORST
• 金额: $ 30.2万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-15 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6856895
• 关键词: Hantavirus; Sin Nombre virus; cardiopulmonary disease; disease /disorder model; enzyme activity; enzyme linked immunosorbent assay; genetically modified animals; hamsters; immunocytochemistry; laboratory mouse; model design /development; nitric oxide synthase; pulmonary edema; virus infection mechanism

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.

描述（由申请人提供）：汉坦病毒心肺综合征（HCP）是一种经常致命的人畜共患病，在美洲流行。 Andes病毒（ANDV）和其他引起HCP的汉坦病毒是NIAID优先病原体（C类）。需要HCP的实验室模型来阐明HCP的发病机理，并严格评估候选疗法对该疾病的疗效。该应用的广泛目的是扩展和完善我们对HCP啮齿动物模型中汉坦病毒感染的发病机理的了解。该应用的第一个目的是表征仓鼠中ANDV感染的进程（尤其是与致命结局之前或同时恰逢鼠标生理事件），评估ANDV感染在仓鼠心脏中的影响，并确定ANDV是否实质上比Maporal病毒更具致命性。将来的研究将使用病毒之间的致死性差异，以阐明人类疾病仓鼠模型中汉坦病毒感染的病毒决定因素。第二个目的是评估诱导型一氧化氮合酶在实验室小鼠中HCPS样疾病发病机理中的作用。一项初步研究的结果表明，感染肺和心脏组织的剧烈氧化反应是实验室小鼠中HCPS样疾病进展的至关重要的。将进行一系列研究，以测试在缺乏诱导型一氧化氮合酶的基因敲除小鼠中ANDV和MAPV的致病性和毒力。严重或致死性HCP的小鼠模型可以实质上增加有关毛细血管泄漏发病机理的研究，从而导致威胁生命的肺水肿HCP。