Modeling COVID-19 in Mice

Researchers developed a mouse model of SARS-CoV-2 infection that reproduces features observed in human patients with COVID-19. Their work was published yesterday in Cell Host & Microbe.

The researchers used CRIPSR/Cas9 to generate a new mouse model that can express hACE2. In the new model, hACE2 is inserted precisely into a specific site on the X chromosome and completely replaces the mouse version of the protein. Additionally, the viral RNA loads in the lung are much higher, and the resulting distribution of hACE2 in various tissues better matches that observed in humans.

After being infected with SARS-CoV-2 through the nose, the genetically engineered mice showed evidence of robust viral RNA replication in the lung, trachea, and brain. SARS-CoV-2 S protein, which binds to hACE2 to enter host cells, was also present in the lung tissue and brain cells. Moreover, the researchers identified the major airway cells targeted by SARS-CoV-2 as Clara cells that produce the protein CC10.

The mice also developed interstitial pneumonia, which affects the tissue and space around the air sacs of the lungs. This causes the infiltration of inflammatory cells, the thickening of the structure that separates air sacs, and blood vessel damage. Compared with young mice, older mice showed more severe lung damage and increased production of cytokines. Taken together, these features mimic those observed in COVID-19 patients.

When the researchers administered SARS-CoV-2 into the stomach, two of the three mice showed high levels of viral RNA in the trachea and lung. The S protein was also present in lung tissue, which showed signs of inflammation. According to the authors, these findings are consistent with the observation that patients with COVID-19 sometimes experience gastrointestinal symptoms such as diarrhea, abdominal pain, and vomiting. But 10 times the dose of SARS-CoV-2 was required to establish infection through the stomach than through the nose.

Future studies using this mouse model may shed light on how SARS-CoV-2 invades the brain and how the virus survives the gastrointestinal environment and invades the respiratory tract. “The hACE2 mice described in our manuscript provide a small animal model for understanding unexpected clinical manifestations of SARS-CoV-2 infection in humans,” says co–senior author Chang-Fa Fan of the National Institutes for Food and Drug Control (NIFDC) in Beijing, China. “This model will also be valuable for testing vaccines and therapeutics to combat SARS-CoV-2.”