Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling

J Exp Med. 2020 Dec 7;217(12):e20201241. doi: 10.1084/jem.20201241.


Severe acute respiratory syndrome-coronavirus 2 (SARS-Cov-2) has caused over 13,000,000 cases of coronavirus disease (COVID-19) with a significant fatality rate. Laboratory mice have been the stalwart of therapeutic and vaccine development; however, they do not support infection by SARS-CoV-2 due to the virus's inability to use the mouse orthologue of its human entry receptor angiotensin-converting enzyme 2 (hACE2). While hACE2 transgenic mice support infection and pathogenesis, these mice are currently limited in availability and are restricted to a single genetic background. Here we report the development of a mouse model of SARS-CoV-2 based on adeno-associated virus (AAV)-mediated expression of hACE2. These mice support viral replication and exhibit pathological findings found in COVID-19 patients. Moreover, we show that type I interferons do not control SARS-CoV-2 replication in vivo but are significant drivers of pathological responses. Thus, the AAV-hACE2 mouse model enables rapid deployment for in-depth analysis following robust SARS-CoV-2 infection with authentic patient-derived virus in mice of diverse genetic backgrounds.

Publication types

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

MeSH terms

  • Angiotensin-Converting Enzyme 2
  • Animals
  • Betacoronavirus / metabolism*
  • COVID-19
  • Cell Line, Tumor
  • Coronavirus Infections / metabolism*
  • Coronavirus Infections / pathology
  • Coronavirus Infections / virology
  • Dependovirus / genetics
  • Disease Models, Animal*
  • Female
  • Humans
  • Inflammation / metabolism
  • Interferon Type I / metabolism*
  • Lung / pathology
  • Lung / virology
  • Male
  • Mice / genetics*
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Pandemics
  • Parvoviridae Infections / metabolism
  • Parvoviridae Infections / virology
  • Peptidyl-Dipeptidase A / genetics
  • Peptidyl-Dipeptidase A / metabolism*
  • Pneumonia, Viral / metabolism*
  • Pneumonia, Viral / pathology
  • Pneumonia, Viral / virology
  • SARS-CoV-2
  • Signal Transduction / genetics
  • Virus Replication / genetics


  • Interferon Type I
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Ace2 protein, mouse
  • Angiotensin-Converting Enzyme 2