Comparison of transgenic and adenovirus hACE2 mouse models for SARS-CoV-2 infection

Emerg Microbes Infect. 2020 Dec;9(1):2433-2445. doi: 10.1080/22221751.2020.1838955.

Abstract

Severe acute respiratory syndrome CoV-2 (SARS-CoV-2) is currently causing a worldwide pandemic with high morbidity and mortality. Development of animal models that recapitulate important aspects of coronavirus disease 2019 (COVID-19) is critical for the evaluation of vaccines and antivirals, and understanding disease pathogenesis. SARS-CoV-2 has been shown to use the same entry receptor as SARS-CoV-1, human angiotensin-converting enzyme 2 (hACE2) [1-3]. Due to amino acid differences between murine and hACE2, inbred mouse strains fail to support high titer viral replication of SARS-CoV-2 virus. Therefore, a number of transgenic and knock-in mouse models, as well as viral vector-mediated hACE2 delivery systems have been developed. Here we compared the K18-hACE2 transgenic model to adenovirus-mediated delivery of hACE2 to the mouse lung. We show that K18-hACE2 mice replicate virus to high titers in the nasal turbinates, lung and brain, with high lethality, and cytokine/chemokine production. In contrast, adenovirus-mediated delivery results in viral replication to lower titers limited to the nasal turbinates and lung, and no clinical signs of infection. The K18-hACE2 model provides a stringent model for testing vaccines and antivirals, whereas the adenovirus delivery system has the flexibility to be used across multiple genetic backgrounds and modified mouse strains.

Keywords: ACE2; COVID-19; SARS-CoV-2; adenovirus; mouse models.

Publication types

  • Comparative Study

MeSH terms

  • A549 Cells
  • Adenoviridae / genetics
  • Angiotensin-Converting Enzyme 2
  • Animals
  • Betacoronavirus / growth & development*
  • Betacoronavirus / metabolism
  • COVID-19
  • Cell Line
  • Chlorocebus aethiops
  • Coronavirus Infections / pathology*
  • Disease Models, Animal
  • Female
  • Humans
  • Lung / pathology
  • Lung / virology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Pandemics
  • Peptidyl-Dipeptidase A / genetics*
  • Pneumonia, Viral / pathology*
  • SARS Virus / growth & development*
  • SARS Virus / metabolism
  • SARS-CoV-2
  • Vero Cells
  • Virus Attachment
  • Virus Replication / genetics*

Substances

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