The new mouse model shows promise as a testbed for COVID-19 vaccines and therapies because it appears to be able to reproduce the viral replication as well as the clinical outcomes observed in human COVID-19 patients.
In humans, SARS-CoV-2 enters host cells by binding to angiotensin-converting enzyme 2 (ACE2), an enzyme attached to the cell membrane. However, due to structural differences in mouse ACE2 compared to human ACE2, mice are less susceptible to SARS-CoV-2 infection. Until now, efforts to study virus infection in mice have used transgenic mice engineered to express human ACE2.
The new paper describes a different approach. The researchers, who are affiliated with various institutions in Beijing and Shanghai, China, generated a new strain of SARS-CoV-2 that was able to replicate and cause disease directly in unmodified mice.
To do this, they repeatedly introduced SARS-CoV-2 into mice through intranasal inoculation until they obtained a mutant version of the virus they called MASCp6 (which stands for "mouse-adapted strain at passage 6"). The mutant version was able to replicate efficiently in the trachea and lungs of the mice and cause the same interstitial pneumonia and inflammatory responses observed in human COVID-19 patients.
The researchers also found that aged mice developed more severe lung damage than young mice, mirroring the age-skewed pattern found in human COVID-19 cases.
Deep sequencing of the genome of the MASCp6 strain revealed five mutations from its parental strain, which was a human clinical isolate of SARS-CoV-2 (BetaCov/human/CHN/Beijing_IME-BJ05/2020). One particular mutation (N501Y) in the spike protein in the virus's receptor-binding domain is likely responsible for its ability to bind to mouse ACE2 cells.
To demonstrate the utility of the new mouse model for testing vaccine candidates, the researchers immunized female mice with two doses of a COVID-19 vaccine candidate and then infected them with the MASCp6 strain of SARS-CoV-2. The immunized mice showed a significant reduction in viral RNA loads (approximately 1,000-fold) in the lungs compared with the control mice.
Furthermore, no apparent pathological lung damage was observed in the immunized mice, whereas inflammatory lung injuries and thickened alveolar septa were observed in the control animals.
The authors noted that the mouse-adapted strain and associated challenge model could be of value in evaluating vaccines and antivirals against SARS-CoV-2.
The new mouse model of infection adds to the existing repertoire of animal models available for studying SARS-CoV-2 infection. Nonhuman primates, which are closest to humans phylogenetically, have also been used as a model of SARS-CoV-2 infection and to test vaccine candidates. Hamsters, ferrets, and cats are also susceptible to SARS-CoV-2 infection and exhibit human-like clinical outcomes following infection.
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