Abstract Coronaviridae are significant human pathogens, as evidenced by several outbreaks of severe respiratory infections in the past 20 years and culminating with the COVID-19 pandemic. Mouse models of COVID-19 have included transgenic expression of the main SARS coronavirus entry receptor on human cells, human angiotensin-convertase 2 (hACE2). However, the original hACE2-Tg mouse strain overexpresses many copies of the transgene, leading to neuropathology not representative of human infection.