Generation of a Humanized mAce2 and a Conditional hACE2 Mouse Models Permissive to SARS-COV-2 Infection

Authors

I-Wen Song
Megan Washington
Carolina Leynes
Jason Hsu
Kempaiah Rayavara
Yangjin Bae
Nele Haelterman
Yuqing Chen
Ming-Ming Jiang
Aleksandra Drelich
Vivian Tat
Denise G Lanza
Isabel Lorenzo
Jason D Heaney
Chien-Te Kent Tseng
Brendan Lee
Ronit Marom

Language

English

Publication Date

6-1-2024

Journal

Mammalian Genome

DOI

10.1007/s00335-024-10033-8

PMID

38488938

PMCID

PMC11955088

PubMedCentral® Posted Date

3-30-2025

PubMedCentral® Full Text Version

Author MSS

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.

Keywords

Animals, Angiotensin-Converting Enzyme 2, COVID-19, Mice, Humans, Disease Models, Animal, SARS-CoV-2, Mice, Transgenic, Lung, Gene Knock-In Techniques, ACE2, Rosa26 hACE2, SARS-CoV-2, preclinical mouse model

Published Open-Access

yes

Recommended Citation

Song, I-Wen; Washington, Megan; Leynes, Carolina; et al., "Generation of a Humanized mAce2 and a Conditional hACE2 Mouse Models Permissive to SARS-COV-2 Infection" (2024). Faculty and Staff Publications. 4999.
https://digitalcommons.library.tmc.edu/baylor_docs/4999