CRISPR’ed Mouse Mimics COVID-19 In Humans

Scientists have used gene editing to create mice expressing human ACE2, the receptor used by SARS-CoV-2 to enter cells.

AsianScientist (Jun. 12, 2020) – Researchers in China have used CRISPR/Cas9 gene editing to create a mouse model of SARS-CoV-2 to aid research on the virus that causes COVID-19. Their findings have been published in Cell Host & Microbe

“A small animal model that reproduces the clinical course and pathology observed in COVID-19 patients is highly needed,” said co-senior study author Dr. Wang You-Chun of the National Institutes for Food and Drug Control (NIFDC), China. “The animal model described here provides a useful tool for studying SARS-CoV-2 infection and transmission. ”

To create the mouse model, the researchers used CRISPR/Cas9 to generate mice that express human angiotensin-converting enzyme II (hACE2), the receptor that SARS-CoV-2 binds to and uses to enter human cells. Instead of being randomly inserted, hACE2 was inserted precisely into a specific site on the X chromosome, completely replacing the mouse version of the protein.

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. Moreover, 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.

“The presence of viral RNAs in brain was somewhat unexpected, as only a few COVID-19 patients have developed neurological symptoms,” said co-senior study author Dr. Qin Cheng-Feng of the Academy of Military Medical Sciences (AMMS), China.

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.

In addition, the mice developed interstitial pneumonia, which affects the tissue and space around the air sacs of the lungs, causing 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 signaling molecules called cytokines. Taken together, these features recapitulate 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 ten 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,” said co-senior study author Dr. Fan Chang-Fa of NIFDC. “This model will also be valuable for testing vaccines and therapeutics to combat SARS-CoV-2.”

The article can be found at: Sun et al. (2020) A Mouse Model of SARS-CoV-2 Infection and Pathogenesis.


Source: Cell Press; Photo: Shutterstock.
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