Float On: A Modest Mouse for COVID-19
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 pandemic. So far, this pandemic is the unprecedented event of the century, responsible for causing hundreds of thousands of untimely deaths, upending the lives of billions of people, and disrupting the global economy. This calls for substantial collaborative efforts to understand the pathogenesis of COVID-19 and also for the development of safe and effective drug treatments and vaccines.
To understand why SARS-CoV-2 causes disease and identify effective treatments and vaccines, significant intensive research and pre-clinical validation should be done in animals that model the human disease. A mouse model of COVID-19 would therefore be valuable in these endeavors. A major hurdle, however, consists of the current known mechanism of infection by which human-adapted sarbecoviruses, such as SARS-CoV-2, infect target cells through the human angiotensin converting enzyme 2 (hACE2) receptor. In mice, the homologous receptors on the respective target cells are sufficiently distinct from the hACE2 receptors such that mice cannot be readily infected with human-adapted sarbecoviruses.
In a recent study published in Nature by Bao et al., mice genetically engineered to express hACE2 receptors were shown to be permissive to viral infection and foster viral replication by SARS-CoV-2 while mice that do not express hACE2 were not. Infectious virus could be readily isolated from the lungs of the hACE2-bearing mice within the first 5 days of infection. The hACE2-bearing mice lost a significant amount of weight and developed inflammation of the lungs within the first week of SARS-CoV-2 infection, similar to the human disease. The mice were also shown to develop an antibody response to the SARS-CoV-2 envelope Spike protein. Thus, hACE2-bearing mice can be infected with SARS-CoV-2, develop lung pathology to the infection, and are immuno-competent. Taken together, this study represents the first mouse model of COVID-19.
It is worth noting that the hACE2-bearing mice were originally made for modeling SARS, the disease caused by SARS-CoV-1 during the 2003-2004 outbreak. Compared to the fatality rate of COVID-19, SARS resulted in a high fatality rate of around 9-11%. Previously in a study by McCray, Jr. et al. in the Journal of Virology, it was shown that hACE2-bearing mice were entirely lethally susceptible to SARS-CoV-1 infection. The hACE2-bearing mice also developed very severe inflammation in the lungs and other organs. Therefore, hACE2-bearing mice exhibit more serious disease to infection by SARS-CoV-1 than by SARS-CoV-2. This makes sense – SARS was a more lethal illness compared to COVID-19. Administration of the monoclonal antibody Mab 201, which targets the Spike protein of SARS-CoV-1, was sufficient to completely prevent weight loss and lethality in hACE2-bearing mice to SARS-CoV-1 infection, illustrating the utility of these mice in evaluation of a SARS therapy. This is strong evidence that hACE2-bearing mice may also be useful in evaluating COVID-19 therapies or vaccines.
Interestingly, in the Bao et al. study, none of the hACE2-bearing mice succumbed to SARS-CoV-2 infection and the inflammation was also generally mild in these mice. One possibility could be that the mice studied were all relatively young. One future direction would be to address whether disease development would be worse in older mice, since COVID-19 disproportionately affects older people. Another possibility could be the fact that the hACE2-bearing mice still express the mouse homologous receptor (mACE2) along with hACE2. One can guess that a mouse bearing only hACE2 receptors might exhibit worse disease development compared to hACE2-bearing mice that still carry the mACE2 receptors. Still, the hACE2-bearing mice provide scientists with one more weapon in the arsenal for fighting the COVID-19 pandemic.
Overall, hACE2-bearing mice will likely be critical for scientists to understand the disease caused by SARS-CoV-2 and to evaluate rapidly drug and vaccine candidates. Though other small animal models of viral infection will also be useful, once again the modest mouse is elevated to its rightful pedestal in the modeling and understanding of an infectious disease.
by Carlos A. Castellanos
Links to the Studies:
Advertisement for the hACE2 transgenic mouse from Jackson labs