RT Journal Article SR Electronic T1 Ferrets not infected by SARS-CoV-2 in a high-exposure domestic setting JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.08.21.254995 DO 10.1101/2020.08.21.254995 A1 Kaitlin Sawatzki A1 Nichola Hill A1 Wendy Puryear A1 Alexa Foss A1 Jonathon Stone A1 Jonathan Runstadler YR 2020 UL http://biorxiv.org/content/early/2020/08/22/2020.08.21.254995.abstract AB Ferrets (Mustela putorius furo) are mustelids of special relevance to laboratory studies of respiratory viruses and have been shown to be susceptible to SARS-CoV-2 infection and onward transmission. Here, we report the results of a natural experiment where 29 ferrets in one home had prolonged, direct contact and constant environmental exposure to two humans with symptomatic COVID-19. We observed no evidence of SARS-CoV-2 transmission from humans to ferrets based on RT-PCR and ELISA. To better understand this discrepancy in experimental and natural infection in ferrets, we compared SARS-CoV-2 sequences from natural and experimental mustelid infections and identified two surface glycoprotein (Spike) mutations associated with mustelids. While we found evidence that ACE2 provides a weak host barrier, one mutation only seen in ferrets is located in the novel S1/S2 cleavage site and is computationally predicted to decrease furin activity. These data support that host factors interacting with the novel S1/S2 cleavage site may be a barrier in ferret SARS-CoV-2 susceptibility and that domestic ferrets are at low risk of natural infection from currently circulating SARS-CoV-2. This may be overcome in laboratory settings using concentrated viral inoculum, but the effects of ferret host-adaptations require additional investigation.Competing Interest StatementThe authors have declared no competing interest.