A tissue specific-infection mouse model of SARS-CoV-2

Animal models play crucial roles in the rapid development of vaccines/drugs for the prevention and therapy of COVID-19, but current models have some deficits when studying the pathogenesis of SARS-CoV-2 on some special tissues or organs. Here, we generated a human ACE2 and SARS-CoV-2 N-F/F knockin mouse line that constitutively expresses human ACE2 and specifically expresses SARS-CoV-2 N gene induced by Cre-recombinase. By crossing with Cre transgenic lines allowing for lung-specific and constitutive expression, we generated lung-specific (Sftpc-hACE2-N-F/F) and constitutive SARS-CoV-2 N (EIIa-hACE2-N-F/F) expressing mice. Upon intranasal infection with a SARS-CoV-2 GFP/Delta N strain which can only replicate in SARS-CoV-2 N expressed cells, we demonstrated that both the Sftpc-hACE2-N-F/F and EIIa-hACE2-N-F/F mice support viral replication. Consistent with our design, viral replication was limited to the lung tissues in Sftpc-hACE2-N-F/F mice, while the EIIa-hACE2-N-F/F mice developed infections in multiple tissues. Furthermore, our model supports different SARS-CoV-2 variants infection, and it can be successfully used to evaluate the effects of therapeutic monoclonal antibodies (Ab1F11) and antiviral drugs (Molnupiravir). Finally, to test the effect of SARS-CoV-2 infection on male reproduction, we generated Sertoli cell-specific SARS-CoV-2 N expressed mice by crossing with AMH-Cre transgenic line. We found that SARS-CoV-2 GFP/Delta N strain could infect Sertoli cells, led to spermatogenic defects due to the destruction of blood-testis barrier. Overall, combining with different tissue-specific Cre transgenic lines, the human ACE2 and SARS-CoV-2 N-F/F line enables us to evaluate antivirals in vivo and study the pathogenesis of SARS-CoV-2 on some special tissues or organs.

Automated summary

This study generated a mouse model expressing human ACE2 and SARS-CoV-2 N gene, allowing for the study of SARS-CoV-2 pathogenesis in specific tissues or organs. The model supports infection by different SARS-CoV-2 variants and can be used to evaluate the effectiveness of antiviral drugs.