 1-year-old BALB/c mice were infected with SARS-CoV-2 MA.  The following key results were observed:

- older mice exhibited a significant weight loss that was not seen in younger mice
- unlike younger mice, older mice had detectable virus in their lungs 4 days post infection (dpi)
- PenH was significantly increased and Rpef was significantly decreased in older mice at 2 dpi

Michigan State University

SARS-CoV-2 S protein is different than other coronaviruses at amino acid residue position 498. Molecular modeling projections suggest that this difference at position 498 would cause SARS-CoV-2 S protein to not efficiently to bind to the regional binding domain of mACE2. Glutamine 498 was replaced with tyrosine, and proline 499 was replaced with threonine from the WIV1 and SARS-CoV-1 viruses. This led to the creation of the recombinant virus SARS-CoV-2 MA.  Experiments have revealed that this recombinant virus can use murine ACE2 (mACE2) for in vitro infection models, and it does not grow more efficiently than the wild type virus in human cells.  

SARS-CoV-2 MA Recombinant SARS-CoV-2 Virus

Dinnon, K. H., Leist, S. R., Schäfer, A., Edwards, C. E., Martinez, D. R., Montgomery, S. A., ... & Gully, K. L. (2020). A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures. Nature, 1-9.
https://www.nature.com/articles/s41586-020-2708-8
doi: 10.1038/s41586-020-2708-8

A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures

Whole body plethysmography (WBP) was used to assess pulmonary function in young mice infected with SARS-CoV-2 MA.  Significance was determined using a 2-way ANOVA and Dunnett's multiple comparisons.  Error bars represent the standard error.  Red lines indicate the transgenic virus, and black lines indicate the WT virus.  PenH slightly but significantly increased in mice infected with the MA virus whereas Rpef significantly decreased on 2 days post infection (dpi).  This suggests that the mice had impaired lung function at this time point.  

SARS-CoV-2 MA Leads to Impaired Lung Function in Young Mice

Young mice infected with SARS-CoV-2 MA were shown to have  insterstitial congestion, epithelial damage, inflammatory infiltrate, and peribronchiolar lympocytic inflammation in their airways starting on 2 days post infection (dpi).  These were shown to be the primary targets of the virus.  The virus was also present in the nasal turbinate epithelium on 2 dpi.  These results mirror the trend of the virus replicating in both the upper and lower airways of humans.  

- Figure F: 2 dpi lung sections
- Figure G: 4 dpi lung sections
- Figure H: 2 dpi nasal turbinates

Histological samples were stained with immunohistochemistry staining (IHC) to visualize viral nucleocapsid protein, and then they were counterstained with hematoxylin and eosin (H&E).  

SARS-CoV-2 MA Efficiently Replicates in the Upper and Lower Airways of Young Mice

SARS-CoV-2 MA Has Exacerbated Effects in Older Mice

Pegylated human interferon lambda-1 (peg-IFN-λ1) is an antiviral drug that is currently in phase-3 of development that could be used to treat COVID-19 patients.  1-year old BALB/c mice were treated with 2µg peg-IFN-λ1 18 hours before or 12 hours after infection with SARS-CoV-2 MA.  It was demonstrated that both prophylactic and therapeutic administration of peg-IFN-λ1 protected lung function (as demonstrated by PenH and Rpef).  

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