PT - JOURNAL ARTICLE AU - Jie Zhou AU - Thomas P. Peacock AU - Jonathan C. Brown AU - Daniel H. Goldhill AU - Ahmed M.E. Elrefaey AU - Rebekah Penrice-Randal AU - Vanessa M. Cowton AU - Giuditta De Lorenzo AU - Wilhelm Furnon AU - William T. Harvey AU - Ruthiran Kugathasan AU - Rebecca Frise AU - Laury Baillon AU - Ria Lassaunière AU - Nazia Thakur AU - Giulia Gallo AU - Hannah Goldswain AU - I’ah Donovan-Banfield AU - Xiaofeng Dong AU - Nadine P. Randle AU - Fiachra Sweeney AU - Martha C. Glynn AU - Jessica L. Quantrill AU - Paul F. McKay AU - Arvind H. Patel AU - Massimo Palmarini AU - Julian A. Hiscox AU - Dalan Bailey AU - Wendy S. Barclay TI - Mutations that adapt SARS-CoV-2 to mustelid hosts do not increase fitness in the human airway AID - 10.1101/2021.08.20.456972 DP - 2021 Jan 01 TA - bioRxiv PG - 2021.08.20.456972 4099 - http://biorxiv.org/content/early/2021/08/20/2021.08.20.456972.short 4100 - http://biorxiv.org/content/early/2021/08/20/2021.08.20.456972.full AB - SARS-CoV-2 has a broad mammalian species tropism infecting humans, cats, dogs and farmed mink. Since the start of the 2019 pandemic several reverse zoonotic outbreaks of SARS-CoV-2 have occurred in mink, one of which reinfected humans and caused a cluster of infections in Denmark. Here we investigate the molecular basis of mink and ferret adaptation and demonstrate the spike mutations Y453F, F486L, and N501T all specifically adapt SARS-CoV-2 to use mustelid ACE2. Furthermore, we risk assess these mutations and conclude mink-adapted viruses are unlikely to pose an increased threat to humans, as Y453F attenuates the virus replication in human cells and all 3 mink-adaptations have minimal antigenic impact. Finally, we show that certain SARS-CoV-2 variants emerging from circulation in humans may naturally have a greater propensity to infect mustelid hosts and therefore these species should continue to be surveyed for reverse zoonotic infections.Competing Interest StatementThe authors have declared no competing interest.