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ORIGINAL RESEARCH article

Front. Microbiol.

Sec. Infectious Agents and Disease

Volume 16 - 2025 | doi: 10.3389/fmicb.2025.1680273

Generation and Characterization of a Humanized ACE2 rat model for the Study of SARS-CoV-2 and COVID-19

Provisionally accepted
Rachel M OlsonRachel M Olson1Henda NabliHenda Nabli2Bettina A GentryBettina A Gentry3Daniel DavisDaniel Davis4Craig L. FranklinCraig L. Franklin2Mary L ShawMary L Shaw2Elizabeth BrydaElizabeth Bryda5*
  • 11Department of Pathobiology and Integrative Biomedical Sciences, College of Veterinary Medicine; 2 Laboratory for Infectious Disease Research, University of Missouri, Columbia, United States
  • 21Department of Pathobiology and Integrative Biomedical Sciences, College of Veterinary Medicine; 3Rat Resource & Research Center, University of Missouri, Columbia, United States
  • 31Department of Pathobiology and Integrative Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, United States
  • 41Department of Pathobiology and Integrative Biomedical Sciences, College of Veterinary Medicine; 4 Animal Modeling Core, University of Missouri, Columbia, United States
  • 51Department of Pathobiology and Integrative Biomedical Sciences, College of Veterinary Medicine; 3Rat Resource & Research Center; 4 Animal Modeling Core, University of Missouri, Columbia, United States

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Our goal was to generate new rat strains for the study of human pathogenic viruses such as SARS-CoV-2 that use ACE2 for entry into host cells. An over-expression rat model was generated using random transgenesis to integrate copies of human ACE2 under the control of the ubiquitously expressed CAG promoter into the rat genome. After transgene copy number, mRNA, and protein expression were confirmed, rats were challenged with the SARS-CoV-2 isolate USA-WA1/2020. Wild type rats are not susceptible to high titer challenge, while rats hemizygous for the ACE2 transgene lost significant body weight and displayed overt clinical signs of infection. This rat model will advance the understanding of COVID-19 and SARS-CoV-2 pathogenesis as well as accelerate the development of vaccines and antiviral therapies and can serve as an animal model for studies of the physiological role of ACE2.

Keywords: ACE2, rat, SARS-CoV-2, COVID-19, animal model, transgenics

Received: 07 Aug 2025; Accepted: 15 Oct 2025.

Copyright: © 2025 Olson, Nabli, Gentry, Davis, Franklin, Shaw and Bryda. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Elizabeth Bryda, brydae@missouri.edu

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Supplementary Material