Date: 1st June 2020
Article in brief:
Small animal models that reproduce the clinical course and pathology observed in COVID-19 patients are highly sought after as they are essential to test potential drugs and vaccines. Now scientists have engineered a humanised mouse model for SARS-CoV-2 infection and pathogenesis in which they replace the endogenous murine ACE2 gene with the human counterpart.
Model organisms are an integral part of the workflow for vaccine and drug discovery programmes. However, it has been shown that animals vary in their susceptibility to SARS-CoV-2 (COVID-19), as do different cells types, and it is thought this may be due to variations in the expression of the viral entry receptor located on the host cell – angiotensin-converting enzyme 2 (ACE2) receptor.
Whilst, this recent work had suggested that ferrets might make a useful model for COVID-19 the researchers, however, did find that some of the pathologies of COVID-19 in humans were not recapitulated. Now, scientists from Bejing, China, have generated a humanised mouse model using CRISPRs to replace the mouse ACE2 (mACE2) receptor for the human version with the aim of mimicking the human pathology of the disease more closely.
- CRISPR-Cas9 was used to insert the human ACE2 (hACE2) receptor with a fluorescent tag into the first coding exon of the mACE2 receptor, thereby disrupting endogenous expression from the mouse gene.
- From those founders the team then went on to establish a homozygous mouse model that stably expressed hACE2 under the control of mACE2 promoter.
- The hACE2 mice were highly susceptible to intranasal infection of SARS-CoV-2 compared to wild type mice, and robust viral RNA replication was seen in the lungs, trachea and the brain.
- hACE2 mice developed interstitial pneumonia upon SARS-CoV-2 infection.
- Interestingly, more lesions of the alveolar epithelial cells and focal haemorrhages were observed in infected aged mice compared with young mice, whilst both showed an increase in neutrophil and macrophage infiltration into the lungs over wild types.
- Cytokine analysis showed that SARS-CoV-2 infected mice had elevated cytokine levels compared to wild type mice; these were particularly high in the aged mice.
- SARS-CoV-2 established productive infections when introduced intragastrically.
Conclusions and future applications:
The team here have generated a humanised mouse model to study the effects of COVID-19, which could prove to be a highly useful tool for accelerating drug and vaccine discovery.
The tissue distribution of hACE2 in the mouse model predominantly matched the clinical findings from COVID-19 patients with, for example, high levels of hACE2 expression being detected in the lungs.
This study was also able to recapitulate age as a risk factor for more pronounced pathology, as in humans, where COVID-19 is particularly dangerous for the elderly. More severe pathological changes were observed in aged mice, such as an increased cytokine and inflammatory response. Although it should be noted that none of the mice died during the experiments.
One surprising observation was the finding of viral RNAs in the brain as few COVID-19 patients have so far reported neurological problems. Whether this is specific to mice, or yet to be more thoroughly evaluated in humans remains to be seen.
SARS-CoV-2 mainly transmits via droplets through an intranasal route. However, there has been reports of gastrointestinal symptoms in infected patients and viral RNAs are also present in faeces of patients. Therefore, there is a possibility of faecal-oral transmission, and the work here certainly supports this theory – SARS-CoV-2 could establish productive infection via an intragastric route in hACE2 mice and lead to pulmonary pathological changes. Although it should be noted that this route was far less efficient at transmission compared with the intranasal inoculations.
It is hoped that this humanised mouse model will be a valuable model for studying COVID-19 disease progression, infectivity, and transmission. It is likely it will help in the understanding of unexpected clinical manifestations of SARS-CoV-2 infections in humans and will be powerful tool for testing potential therapeutics and vaccines to combat the virus.
Sun, S.-H., Q. Chen, H.-J. Gu, G. Yang, Y.-X. Wang, X.-Y. Huang, S.-S. Liu, N.-N. Zhang, X.-F. Li, R. Xiong, Y. Guo, Y.-Q. Deng, W.-J. Huang, Q. Liu, Q.-M. Liu, Y.-L. Shen, Y. Zhou, X. Yang, T.-Y. Zhao, C.-F. Fan, Y.-S. Zhou, C.-F. Qin and Y.-C. Wang (2020). “A mouse model of SARS-CoV-2 infection and pathogenesis.” Cell Host & Microbe.
https://doi.org/10.1016/j.chom.2020.05.020
