The K18-Human ACE2 Transgenic Mouse Model Recapitulates Non-severe and Severe COVID-19 in Response to an Infectious Dose of the SARS-CoV-2 Virus

Wenjuan Dong, Heather Mead, Lei Tian, Jun Gyu Park, Juan I. Garcia, Sierra Jaramillo, Tasha Barr, Daniel S. Kollath, Vanessa K. Coyne, Nathan E. Stone, Ashley Jones, Jianying Zhang, Aimin Li, Li Shu Wang, Martha Milanes-Yearsley, Jordi B. Torrelles, Luis Martinez-Sobrido, Paul S. Keim, Bridget Marie Barker, Michael A. CaligiuriJianhua Yu

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

A comprehensive analysis and characterization of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection model that mimics non-severe and severe coronavirus disease 2019 (COVID-19) in humans is warranted for understating the virus and developing preventive and therapeutic agents. Here, we characterized the K18-hACE2 mouse model expressing human (h)ACE2 in mice, controlled by the human keratin 18 (K18) promoter, in the epithelia, including airway epithelial cells where SARSCoV- 2 infections typically start. We found that intranasal inoculation with higher viral doses (2 × 103 and 2 × 104 PFU) of SARS-CoV-2 caused lethality of all mice and severe damage of various organs, including lung, liver, and kidney, while lower doses (2 × 101 and 2 × 102 PFU) led to less severe tissue damage and some mice recovered from the infection. In this hACE2 mouse model, SARS-CoV-2 infection damaged multiple tissues, with a dose-dependent effect in most tissues. Similar damage was observed in postmortem samples from COVID-19 patients. Finally, the mice that recovered from infection with a low dose of virus survived rechallenge with a high dose of virus. Compared to other existing models, the K18-hACE2 model seems to be the most sensitive COVID-19 model reported to date. Our work expands the information available about this model to include analysis of multiple infectious doses and various tissues with comparison to human postmortem samples from COVID-19 patients. In conclusion, the K18-hACE2 mouse model recapitulates both severe and non-severe COVID-19 in humans being dose-dependent and can provide insight into disease progression and the efficacy of therapeutics for preventing or treating COVID-19.

Original languageEnglish (US)
Article numbere00964-21
JournalJournal of Virology
Volume96
Issue number1
DOIs
StatePublished - Jan 2022

Keywords

  • COVID-19
  • Infectious disease
  • K18-hACE2
  • Lung infection
  • Mouse model
  • SARS-CoV-2

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Fingerprint

Dive into the research topics of 'The K18-Human ACE2 Transgenic Mouse Model Recapitulates Non-severe and Severe COVID-19 in Response to an Infectious Dose of the SARS-CoV-2 Virus'. Together they form a unique fingerprint.

Cite this