Summary Animal models of COVID-19 will play a critical role in developing and testing novel vaccines and therapies for this disease, but a very limited number of models are currently available, and they suffer from substantial limitations. The SARS-CoV-2 virus uses human ACE2 to bind to cells, and the host TMPRSS2 protease to prime the viral spike proteins for entry. Three mouse strains expressing human ACE2 as a transgene exist— only one of which is being prepared for distribution in the US and is in high demand under the current circumstance. Furthermore, concerns exist about aberrant expression of human ACE2 in these mice, given the lack of normal regulatory elements, and none of the ACE2 transgenic strains express the human TMPRSS2 protease, thus cannot be used to assess therapeutic strategies that target the protease. We propose to employ a novel and rapid gene replacement strategy that we have pioneered, to generate ACE2 and TMPRSS2 gene replacement mice. Our BSL3 experienced team will infect these mice with SARS-CoV-2 in order to determine if they display the expected viral replication, interstitial pneumonia, inflammatory cytokine storm, and antibody responses that characterize human COVID-19 disease. Importantly, these mice will be immediately sent to our partners at Jackson Labs (JAX) for rapid expansion and world-wide distribution.