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

Abstract

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 NF/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-NF/F) and constitutive SARS-CoV-2 N (EIIa-hACE2-NF/F) expressing mice. Upon intranasal infection with a SARS-CoV-2 GFP/ΔN strain which can only replicate in SARS-CoV-2 N expressed cells, we demonstrated that both the Sftpc-hACE2-NF/F and EIIa-hACE2-NF/F mice support viral replication. Consistent with our design, viral replication was limited to the lung tissues in Sftpc-hACE2-NF/F mice, while the EIIa-hACE2-NF/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/ΔN 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 NF/F line enables us to evaluate antivirals in vivo and study the pathogenesis of SARS-CoV-2 on some special tissues or organs.

A mouse xenograft long‐term replication yields a SARS‐CoV‐2 Delta mutant with increased lethality

“…12 To study the mutability of SARS-CoV-2 and its effects on transmissibility and pathogenicity, a persistent infection model is required, wherein numerous mutant viruses emerge as a result of continuous replication in a defined environment. [13][14][15] Recently, a humanized animal model of SARS-CoV-2 infection was established using adeno-associated virus-mediated human ACE expression, which showed symptoms and immunopathology for up to 28 days, recapitulating the effects of persistent SARS-CoV-2 infection in humans. 14 We recently established a long-term infection model by infecting Calu-3 cell-derived xenograft tumors in severely immunodeficient mice with SARS-CoV-2.…”

“…Currently, used animal models include transgenic mice expressing human ACE2, ferrets, mink, hamsters, and nonhuman primates, which recapitulate clinical symptoms and immune responses against SARS‐CoV‐2 in humans 12 . To study the mutability of SARS‐CoV‐2 and its effects on transmissibility and pathogenicity, a persistent infection model is required, wherein numerous mutant viruses emerge as a result of continuous replication in a defined environment 13–15 . Recently, a humanized animal model of SARS‐CoV‐2 infection was established using adeno‐associated virus‐mediated human ACE expression, which showed symptoms and immunopathology for up to 28 days, recapitulating the effects of persistent SARS‐CoV‐2 infection in humans 14 …”