Animal models of hantavirus cardiopulmonary disease

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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.