SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function

Nat Immunol. 2020 Nov;21(11):1327-1335. doi: 10.1038/s41590-020-0778-2. Epub 2020 Aug 24.

Abstract

Although animal models have been evaluated for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, none have fully recapitulated the lung disease phenotypes seen in humans who have been hospitalized. Here, we evaluate transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor driven by the cytokeratin-18 (K18) gene promoter (K18-hACE2) as a model of SARS-CoV-2 infection. Intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice results in high levels of viral infection in lungs, with spread to other organs. A decline in pulmonary function occurs 4 days after peak viral titer and correlates with infiltration of monocytes, neutrophils and activated T cells. SARS-CoV-2-infected lung tissues show a massively upregulated innate immune response with signatures of nuclear factor-κB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18-hACE2 model of SARS-CoV-2 infection shares many features of severe COVID-19 infection and can be used to define the basis of lung disease and test immune and antiviral-based countermeasures.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Angiotensin-Converting Enzyme 2
  • Animals
  • Betacoronavirus / immunology*
  • COVID-19
  • Chlorocebus aethiops
  • Coronavirus Infections / immunology
  • Coronavirus Infections / pathology*
  • Disease Models, Animal
  • Female
  • Humans
  • Immunity, Innate / immunology*
  • Interferon Type I / immunology
  • Interferon-gamma / immunology
  • Keratin-18 / genetics
  • Leukocytes / immunology
  • Lymphocyte Activation / immunology
  • Male
  • Mice
  • Mice, Transgenic
  • Monocytes / immunology
  • NF-kappa B / immunology
  • Neutrophil Infiltration / immunology
  • Neutrophils / immunology
  • Pandemics
  • Peptidyl-Dipeptidase A / genetics*
  • Pneumonia / genetics
  • Pneumonia / pathology*
  • Pneumonia / virology
  • Pneumonia, Viral / immunology
  • Pneumonia, Viral / pathology*
  • Promoter Regions, Genetic / genetics
  • SARS-CoV-2
  • T-Lymphocytes / immunology
  • Vero Cells
  • Virus Replication / immunology

Substances

  • Interferon Type I
  • Keratin-18
  • NF-kappa B
  • Interferon-gamma
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Ace2 protein, mouse
  • Angiotensin-Converting Enzyme 2