The Mutant Mouse Resource and Research Center at The Jackson Laboratory

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Abstract To date, most of the research using mouse models for COVID-19 has been done using a transgenic mouse model expressing high levels of the human ACE2gene driven by the Keratin-18(K18) promoter. While this model has been extremely useful, it has some notable limitations: disease progression is rapid and invariably fatal within one week, with an uncharacteristically high infection rate in the brain. These features restrict its use to study the biology related to the acute phase of the infection, leaving a gap in models that more accurately reflect the expression patterns and levels of the ACE2 receptor, and that extend the disease course beyond the acute phase of infection. We will employ a refined genetic strategy utilizing a recently published knock-in model of the human ACE2 cDNA into the mouse Ace2 locus. By crossing these hACE2 knock-in mice with inbred Collaborative Cross (CC) founder strains, and by characterizing the response of resulting humanized F1 progeny to live SARS-CoV-2 infection through an established partnership with researchers at the Trudeau Institute, we will test the hypothesis that clinical variation in COVID-19 patient response can be more accurately modelled and phenotypically characterized in mice with naturally regulated ACE2 expression on variable genetic backgrounds. Consistent with the aims of MMRRC parent grant to identify and distribute mouse models to the biomedical community, this proposal aims to rapidly provide the research community with an urgently needed resource for linking the variability in COVID-19 disease outcome with underlying host genetic features, and for developing precision models for post infection sequelae.