Host barriers to SARS-CoV-2 demonstrated by ferrets in a high-exposure domestic setting

Proc Natl Acad Sci U S A. 2021 May 4;118(18):e2025601118. doi: 10.1073/pnas.2025601118.


Ferrets (Mustela putorius furo) are mustelids of special relevance to laboratory studies of respiratory viruses and have been shown to be susceptible to severe acute respiratory syndrome coronavirus 2 (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 disease, one of whom was confirmed positive for SARS-CoV-2. We observed no evidence of SARS-CoV-2 transmission from humans to ferrets based on viral and antibody assays. 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 (S) mutations associated with mustelids. While we found evidence that angiotensin-converting enzyme II 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 cleavage efficiency. These data support the idea 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. We propose two mechanistically grounded hypotheses for mustelid host adaptation of SARS-CoV-2, with possible effects that require additional investigation.

Keywords: SARS-CoV-2; coronavirus; genetics; transmission; virology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Angiotensin-Converting Enzyme 2 / physiology
  • Animals
  • COVID-19 / transmission*
  • Disease Susceptibility
  • Ferrets / virology*
  • Host Adaptation*
  • Humans
  • Mutation*
  • SARS-CoV-2*
  • Spike Glycoprotein, Coronavirus / genetics*


  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Angiotensin-Converting Enzyme 2