RT Journal Article
SR Electronic
T1 The K18-hACE2 Transgenic Mouse Model Recapitulates Non-Severe and Severe COVID-19 in Response to Infectious Dose of SARS-CoV-2 Virus
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.05.08.443244
DO 10.1101/2021.05.08.443244
A1 Wenjuan Dong
A1 Heather Mead
A1 Sierra Jaramillo
A1 Tasha Barr
A1 Daniel S. Kollath
A1 Vanessa K. Coyne
A1 Nathan E. Stone
A1 Ashley Jones
A1 Jianying Zhang
A1 Aimin Li
A1 Li-Shu Wang
A1 Martha Milanes-Yearsley
A1 Paul S Keim
A1 Bridget Marie Barker
A1 Michael Caligiuri
A1 Jianhua Yu
YR 2021
UL http://biorxiv.org/content/early/2021/05/09/2021.05.08.443244.abstract
AB A comprehensive analysis and characterization of a SARS-CoV-2 infection model that mimics non-severe and severe 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 epithelia, including airway epithelial cells where SARS-CoV-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 lungs, 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 humanized hACE2 mouse model, SARS-CoV-2 infection damaged multiple tissues, with a dose-dependent effect in most tissues. Similar damage was observed in biopsy samples from COVID-19 patients. Finally, the mice that recovered after infection with a low dose of virus also 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 biopsy samples from COVID-19 patients. In conclusion, the K18-hACE2 mouse model recapitulates both severe and non-severe COVID-19 in humans and can provide insight into disease progression and the efficacy of therapeutics for preventing or treating COVID-19.Importance The pandemic of COVID-19 has reached 112,589,814 cases and caused 2,493,795 deaths worldwide as of February 23, 2021, has raised an urgent need for development of novel drugs and therapeutics to prevent the spread and pathogenesis of SARS-CoV-2. To achieve this goal, an animal model that recapitulates the features of human COVID-19 disease progress and pathogenesis is greatly needed. In this study, we have comprehensively characterized a mouse model of SARS-CoV-2 infection using K18-hACE2 transgenic mice. We infected the mice with low and high doses of SARS-CoV-2 virus to study the pathogenesis and survival in response to different infection patterns. Moreover, we compared the pathogenesis of the K18-hACE2 transgenic mice with that of the COVID-19 patients to show that this model could be a useful tool for the development of anti-viral drugs and therapeutics.Competing Interest StatementThe authors have declared no competing interest.