A mouse model of COVID-19 that mirrors several features of human disease has been developed using CRISPR–Cas9 knock-in technology. The model is the first to contain only the human version of the angiotensin-converting enzyme 2 (ACE2) — the receptor SARS-CoV-2 uses to enter cells. The new model could shed light on viral infection and transmission, as well as help investigators identify effective treatments and vaccines. Older models of coronavirus infection, developed in response to the 2002–2003 severe acute respiratory syndrome (SARS) epidemic, used transgene expression of human ACE2. Recently developed models use adenovirus-mediated delivery of human ACE2, but both types of model still express mouse ACE2, which doesn’t mediate viral entry, thus limiting their utility.
In the CRISPR–Cas9 version, You-Chun Wang from the National Institutes for Food and Drug Control, Beijing, and collaborators inserted cDNAs of human ACE2 into exon 2 of the mouse Ace2 gene, located on the X chromosome, to abolish mouse Ace2 expression. The human ACE2 gene is under control of mouse Ace2 promoter. The authors note that the tissue distribution of ACE2 matches the clinical symptoms of COVID-19 in humans.
A key advantage of the humanized ACE2 mice over transgene models is that they achieve a much higher viral load (up to 108 copies per gram of tissue) in lung following nasal infection with SARS-CoV-2. In the airway, club cells of the bronchiolar epithelium were the main cell type infected with SARS-CoV-2. The virus was also found in the brain, which is surprising given that few patients with COVID-19 develop neurological symptoms. The pulmonary pathology of the humanized ACE2 mice, characterized by inflammation in the alveolar walls, and an elevated inflammatory cytokine response were greater in aged animals than in younger ones, mirroring what is seen in humans. A drawback of the model, however, is that mice developed only mild infection; no clinical symptoms of COVID-19 or mortality were seen in this humanized ACE2 model.
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A COVID-19 model. Nat Biotechnol 38, 773 (2020). https://doi.org/10.1038/s41587-020-0606-0