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Generation of a humanized mAce2 and a conditional hACE2 mouse models permissive to SARS-COV-2 infection

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Abstract

The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) remains a public health concern and a subject of active research effort. Development of pre-clinical animal models is critical to study viral-host interaction, tissue tropism, disease mechanisms, therapeutic approaches, and long-term sequelae of infection. Here, we report two mouse models for studying SARS-CoV-2: A knock-in mAce2F83Y,H353K mouse that expresses a mouse-human hybrid form of the angiotensin-converting enzyme 2 (ACE2) receptor under the endogenous mouse Ace2 promoter, and a Rosa26 conditional knock-in mouse carrying the human ACE2 allele (Rosa26hACE2). Although the mAce2F83Y,H353K mice were susceptible to intranasal inoculation with SARS-CoV-2, they did not show gross phenotypic abnormalities. Next, we generated a Rosa26hACE2;CMV-Cre mouse line that ubiquitously expresses the human ACE2 receptor. By day 3 post infection with SARS-CoV-2, Rosa26hACE2;CMV-Cre mice showed significant weight loss, a variable degree of alveolar wall thickening and reduced survival rates. Viral load measurements confirmed inoculation in lung and brain tissues of infected Rosa26hACE2;CMV-Cre mice. The phenotypic spectrum displayed by our different mouse models translates to the broad range of clinical symptoms seen in the human patients and can serve as a resource for the community to model and explore both treatment strategies and long-term consequences of SARS-CoV-2 infection.

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Acknowledgements

The SARS-CoV-2 WA1/2020 used in this study was a kind gift from Dr. Natalie Thornburg at the Centers for Disease Control (CDC), Atlanta, GA, through the World Reference Center for Emerging Viruses and Arboviruses (WRCEVA). This project was supported by the Genetically Engineered Rodent Model (GERM) Core at BCM.

Funding

RM was supported by NIH/NIGMS T32GM07526. This project was supported by the Genetically Engineered Rodent Model (GERM) Core at BCM, which is funded in part by the National Institutes of Health Cancer Center Grant (P30 CA125123).

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Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA

    I-Wen Song, Megan Washington, Carolina Leynes, Yangjin Bae, Nele Haelterman, Yuqing Chen, Ming-Ming Jiang, Denise G. Lanza, Isabel Lorenzo, Jason D. Heaney, Brendan Lee & Ronit Marom

  2. Department of Biochemistry, Cell and Molecular Biology, University of Texas Medical Branch, Galveston, TX, 77555, USA

    Jason Hsu

  3. Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, 77555, USA

    Kempaiah Rayavara, Aleksandra Drelich & Chien-Te Kent Tseng

  4. Department of Pathology, University of Texas Medical Branch, Galveston, TX, 77555, USA

    Vivian Tat

Authors
  1. I-Wen Song
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  2. Megan Washington
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  15. Chien-Te Kent Tseng
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  16. Brendan Lee
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  17. Ronit Marom
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Contributions

Conceptualization: IS, JDH, CKT, BL and RM. Methodology & investigation: IS, MW, CL, JH, KR, YC, MJ, AD, VT, DGL, IL and RM. Project administration: YB and NH. Supervision: CKT, BL and RM. Writing—original draft: IS, CKT, BL and RM. Writing—review & editing: All authors reviewed and edited the manuscript.

Corresponding author

Correspondence to Ronit Marom.

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Song, IW., Washington, M., Leynes, C. et al. Generation of a humanized mAce2 and a conditional hACE2 mouse models permissive to SARS-COV-2 infection. Mamm Genome (2024). https://doi.org/10.1007/s00335-024-10033-8

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