Hantaviruses cause significant morbidity and mortality each year from two diseases with similar pathogenesis, hantavirus cardiopulmonary syndrome (HCPS) and hemorrhagic fever with renal syndrome. In each disease, a prominent inflammatory immunopathology occurs without conspicuous damage to the vascular endothelium, which is the principal target of infection. Reservoir rodents are persistently infected for life without sigs of disease, and periodically shed virus in excrement that can be transmitted to humans. Reservoirs produce a high-titered IgG response, including neutralizing antibody, but fail to clear virus. A regulatory T cell response predominates in reservoir hosts and this may limit immunopathology but at the cost of persistent infection to an otherwise innocuous virus. In contrast, Syrian hamsters infected with Andes or Maporal hantaviruses develop an inflammatory disease that parallels human HCPS.The dichotomous outcomes in pathogenic infections of hamsters and nonpathogenic infections of a reservoir host species, the deer mouse, are the focus of this project, which will provide an understanding of the mechanisms governing immunopathology associated with disease or immune evasion without disease. We will determine the quality and magnitude of the immune response in deer mice for clues to biology of hantavirus infections of reservoirs, manipulate the immune responses in deer mice to alter the outcome of infection with hantaviruses, and examine control of infection using reassortant viruses. In addition, we will examine the pathogenic role of the immune response in hamsters by depletion of NK cells that may contribute to pathogenesis, and modulate the immune response in an effort to temper disease as a potential therapy for hantavirus infection. Together, these experiments should provide the clearest picture yet of the ecology of hantaviruses, and may identify therapeutic targets for the treatment of hantavirus disease.