- hACE2 expression was highest in the lungs
- decrease in lung hACE2 expression over time (dpi = days post infection) may be the result of receptor down regulation, receptor shedding, or the death of cells expressing the receptor

Michigan State University

The heterozygous mouse K18-hACE2 (strain: 2B6.Cg-Tg(K18-ACE2)2Prlmn/J) is a transgenic line that expresses human ACE2 (hACE2).  When infected with SARS-CoV-2, this strain was shown to:

- support SARS-CoV-2 infection and replication
- undergo severe pulmonary disease
- lose weight
- have increased concentrations of pro-inflammatory cytokines and chemokines in the lungs
- experience histopathological changes in lung tissue that correlate with disease severity

Many of these observations mirror what is seen in severe SARS-CoV-2 infections in humans.  

K18-hACE2 Mouse Model of COVID-19

Winkler, E. S., Bailey, A. L., Kafai, N. M., Nair, S., McCune, B. T., Yu, J., ... & Ritter, J. H. (2020). SARS-CoV-2 infection in the lungs of human ACE2 transgenic mice causes severe inflammation, immune cell infiltration, and compromised respiratory function. bioRxiv.
https://www.biorxiv.org/content/10.1101/2020.07.09.196188v1
doi: 10.1101/2020.07.09.196188

SARS-CoV-2 infection in the lungs of human ACE2 transgenic mice causes severe inflammation, immune cell infiltration, and compromised respiratory function

hACE2 Expression in K18-hACE2 Mice

This transgenic line does not accurately represent what ACE2 expression is like in humans.  The exogenous promoter cytokeratin-18 is used which results in an expression pattern that is distinct from endogenously produced ACE2.  Because hACE2 is not native to the mouse, its regulatory system cannot influence expression levels.  Additionally, it is difficult to model the comorbidities of severe COVID-19 that influence ACE2 levels (ex: obesity, cardiovascular disease, diabetes mellitus) in a mouse.  

Limitations of the K18-hACE2 Mouse Model of COVID-19

40% of mice were found to have infectious SARS-CoV-2 and viral RNA in their brain tissue. However, 60% had no infectious virus and low levels of viral RNA present. Only 1/6 animals was SARS-CoV-2+ in its brain tissue 7 days after infection (dpi = days post infection). The virus was found throughout the cerebral cortex and seemed to avoid the olfactory bulb and cerebellum. This suggests that SARS-CoV-2 can cross the blood-brain barrier and does not travel across the cribriform plate to infect neuronal processes near the initial infection site in the nose. 

Figure: SARS-CoV-2 RNA staining (red) of one infected mouse brain. RNA is present in the cerebral cortex, and not in cerebellar or olfactory tissue.

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