Mouse model mimics coronavirus infection in humans, may help test drugs: Study

Genetically modified mice infected with the novel coronavirus can reproduce features observed in human patients, according to a study which may lead to a new approach for testing potential COVID-19 drugs. The study, published in the journal Cell Host & Microbe, used gene editing technology to create mice that make human angiotensin-converting enzyme II (hACE2).

According to the researchers, including those from the National Institutes for Food and Drug Control (NIFDC) in China, hACE2 is the receptor that the novel coronavirus, SARS-CoV-2, uses to enter human cells.

"A small animal model that reproduces the clinical course and pathology observed in COVID-19 patients is highly needed," said study co-senior author You-Chun Wang from NIFDC.

The animal model described in the study provides a useful tool for studying SARS-CoV-2 infection and transmission, Wang said.

According to the authors, their mouse model has several advantages compared with other genetically engineered mice that express hACE2.

In the current model, the scientists said, instead of being randomly inserted, hACE2 is inserted precisely into a specific site on the mouse genome, completely replacing the mouse version of the protein.

In addition, they said this process yielded a genetically stable model, with few differences among individual mice.

According to the study, the quantity of the coronavirus genetic material, RNA, in the lungs of mice created this way are much higher.

As a result, the scientists said the resulting distribution of hACE2 in various tissues better matches that observed in humans.

After being infected with SARS-CoV-2 through the nose, they said the mice showed evidence of robust viral RNA replication in the lung, trachea, and brain.

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

SARS-CoV-2 S protein, which binds to hACE2 to enter host cells, was also present in the lung tissue and brain cells, the study noted.
The researchers also identified the major airway cells targeted by the virus.

"Our result provides the first line of evidence showing the major target cells of SARS-CoV-2 in the lung," said Yu-Sen Zhou, another study author from AMMS.

Over the course of the study, the scientists said the mice developed interstitial pneumonia, which affects the tissue and space around the air sacs of the lungs.

Due to this condition, they said there was an infiltration of inflammatory cells, the thickening of the structure that separates air sacs, and blood vessel damage in the mice.

Compared with young mice, the study said older mice showed more severe lung damage and increased production of cell signalling molecules called cytokines.

Taken together, the researchers said these features recapitulate those observed in COVID-19 patients.

When they 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, the study said.

According to the researchers, the findings are consistent with the observation that patients with COVID-19 sometimes experience gastrointestinal symptoms such as diarrhea, abdominal pain, and vomiting.

However, the study noted that 10 times the dose of SARS-CoV-2 was required to establish infection through the stomach than through the nose.

The scientists said 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 provide a small animal model for understanding unexpected clinical manifestations of SARS-CoV-2 infection, the researchers said, adding that they will also be valuable for testing therapeutics to combat COVID-19.

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