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

Bo Yang; Chao Liu; Xiaohui Ju; Bingbing Wu; Zhuangfei Wang; Fucheng Dong; Yanying Yu; Xiaohui Hou; Min Fang; Fei Gao; Xuejiang Guo; Yaoting Gui; Qiang Ding; Wei Li

doi:10.1038/s41421-023-00536-0

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

Cell Discov. 2023 Apr 20;9(1):43. doi: 10.1038/s41421-023-00536-0.

Authors

Bo Yang^#^{1

2}, Chao Liu^#^{2

3}, Xiaohui Ju^#⁴, Bingbing Wu^{3

5}, Zhuangfei Wang^{2

6}, Fucheng Dong^{3

5}, Yanying Yu⁴, Xiaohui Hou⁶, Min Fang⁷, Fei Gao^{3

5}, Xuejiang Guo⁸, Yaoting Gui⁹, Qiang Ding¹⁰, Wei Li^{11

12}

Affiliations

¹ Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, Guangdong, China.
² Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.
³ State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
⁴ Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, China.
⁵ University of Chinese Academy of Sciences, Beijing, China.
⁶ Zunyi Medical University, Zunyi, Guizhou, China.
⁷ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
⁸ State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.
⁹ Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen PKU-HKUST Medical Center, Shenzhen, Guangdong, China. guiyaoting2007@aliyun.com.
¹⁰ Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, China. qding@tsinghua.edu.cn.
¹¹ Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China. leways@gwcmc.org.
¹² State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. leways@gwcmc.org.

^# Contributed equally.

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 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/ΔN 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/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 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.