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As with other coronaviruses (SARS, MERS) the role of animals is of intense interest. Believed to have originated in bats, the role of other animals in the epidemiology of the SARS-CoV-2 pandemic is still unclear, as is the range of susceptible hosts. American bison were intranasally infected with SARS-CoV-2 and monitored for seroconversion and the presence of viral RNA in oronasal secretions and feces. Although clinical signs were not seen, permissiveness of bison to infection with SARS-CoV-2 was manifest by seroconversion, the presence of viral RNA in oronasal secretions, persistence of viral RNA in lymphoid tissue, and viral associated interstitial pneumonia. Retrospective sequencing of the inoculum revealed a common in vitro adaptation in the furin cleavage site of the spike protein that may have reduced in vivo viral fitness. 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