ace2
an authentic animal model for coronavirus infection
During the COVID-19 pandemic, one of the many challenges faced was a lack of an authentic mouse model of SARS-CoV-2 infection. Due to natural polymorphisms in murine Ace2, the receptor for SARS-CoV-2, the original isolates of the virus such as the Washington strain, are unable to productively infect mice. Similarly, current animal models in which human ACE2 is genetically introduced to mice, e.g. by driving expression with a strong promoter often leads to changes in viral tropism not observed physiologically. Given this, a mouse model that is susceptible to SARS-CoV-2 and has the ability to mimic human disease pathology could be extremely valuable for therapeutic development, as well as for a better basic understanding of human COVID pathophysiology, and the effects of age, immune-suppression status and other factors. Such a model could leverage the enormous genetic resources available for murine-based models and will be valuable for preparedness against potential future disease outbreaks.
We therefore generated a humanized mouse model recapitulating COVID-19 pathology by swapping 72 kb of the mouse Ace2 locus with 116 kb or 180 kb of the human ACE2 genomic region. To do this we used our genome rewriting method mSwAP-In. The subsequently-generated hACE2 GREAT-GEMM (Genomically Rewritten and Tailored GEMM) accurately reflected human-specific aspects of authentic gene expression both at the transcriptional and splicing levels. ACE2-humanized mice were susceptible to SARS-CoV-2 upon intranasal infection, but unlike the transgenic K18-hACE2 model, the animals did not succumb to infection, suggesting that the hACE2 GREAT-GEMM may better model human COVID-19.
Read more in Zhang et al., Nature 2023.
IN COllaboration with:
Benjamin tenOever, PhD, NYU Langone Health
Kamal M. Khanna, PhD, NYU Langone Health