A lethal disease model for hantavirus pulmonary 2 syndrome in immunosuppressed Syrian hamsters 3 infected with Sin Nombre virus

25 Sin Nombre virus (SNV) is a rodent-borne hantavirus that causes hantavirus pulmonary 26 syndrome (HPS) predominantly in North America. SNV infection of immunocompetent 27 hamsters results in an asymptomatic infection; the only lethal disease model for a 28 pathogenic hantavirus is Andes virus (ANDV) infection of Syrian hamsters. Efforts to 29 create a lethal SNV disease model in hamsters by repeatedly passaging virus through 30 the hamster have demonstrated increased dissemination of the virus, yet no signs of 31 disease. In this study we demonstrate that immunosuppression of hamsters through 32 the administration of a combination of dexamethasone and cyclophosphamide, followed 33 by infection with SNV, results in a vascular leak syndrome that accurately mimics both 34 HPS disease in humans and ANDV infection of hamsters. Immunosuppressed 35 hamsters infected with SNV have a mean day-to-death of 13, and display clinical signs 36 associated with HPS including pulmonary edema. Viral antigen was widely detectable 37 throughout the pulmonary endothelium. Histologic analysis of lung sections showed 38 marked inflammation and edema within alveolar septa of SNV infected hamsters, which 39 is similar to what is exhibited by hamsters infected with ANDV. Importantly, SNV40 specific neutralizing polyclonal antibody administered 5 days after SNV conferred 41 significant protection against disease. This experiment not only demonstrated that the 42 disease was caused by SNV; it also demonstrated the utility of this animal model for 43 testing candidate medical countermeasures. This is the first report of lethal disease 44 caused by SNV in an adult small animal model. 45 46 on O cber 8, 2017 by gest http/jvi.asm .rg/ D ow nladed fom