A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures
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Abstract
Coronaviruses are prone to transmission to new host species, as recently demonstrated by the spread to humans of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic 1. Small animal models that recapitulate SARS-CoV-2 disease are needed urgently for rapid evaluation of medical countermeasures 2,3. SARS-CoV-2 cannot infect wild-type laboratory mice owing to inefficient interactions between the viral spike protein and the mouse orthologue of the human receptor, angiotensin-converting enzyme 2 (ACE2)4. Here we used reverse genetics 5 to remodel the interaction between SARS-CoV-2 spike protein and mouse ACE2 and designed mouse-adapted SARS-CoV-2 (SARS-CoV-2 MA), a recombinant virus that can use mouse ACE2 for entry into cells. SARS-CoV-2 MA was able to replicate in the upper and lower airways of both young adult and aged BALB/c mice. SARS-CoV-2 MA caused more severe disease in aged mice, and exhibited more clinically relevant phenotypes than those seen in Hfh4-ACE2 transgenic mice, which express human ACE2 under the control of the Hfh4 (also known as Foxj1) promoter. We demonstrate the utility of this model using vaccine-challenge studies in immune-competent mice with native expression of mouse ACE2. Finally, we show that the clinical candidate interferon-λ1a (IFN-λ1a) potently inhibits SARS-CoV-2 replication in primary human airway epithelial cells in vitro-both prophylactic and therapeutic administration of IFN-λ1a diminished SARS-CoV-2 replication in mice. In summary, the mouse-adapted SARS-CoV-2 MA model demonstrates age-related disease pathogenesis and supports the clinical use of pegylated IFN-λ1a as a treatment for human COVID-19 6.
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In another model of COVID-19 using BALB/c mice, TNFα, IL-1β, and IL-6 were increased in the lung during peak disease, but investigators did not describe the response in the heart.
“In another model of COVID-19 using BALB/c mice, TNF α , IL-1 β , and IL-6 were increased in the lung during peak disease, but investigators did not describe the response in the heart. 180”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [180]
The Age effect on SARS-CoV-2 disease in mice section reports increased lung proinflammatory cytokines at 2 days after infection in aged BALB/c mice. The cytokine-analysis passage lists significant results for TNF-α and IL-6, but lists IL-1α rather than IL-1β; our copy therefore does not establish the claimed IL-1β increase. The passages describe lung and serum responses, not a heart response. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMouse studies of SARS-CoV-2 show a higher viral burden in older mice during the first days after infection.
“Mouse studies of SARS-CoV-2 show a higher viral burden in older mice in the first few days post-infection”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [54]
Ageing may cause a delay or dysfunction in the initial triggering and priming of the immune response to SARS-CoV-2.
“suggesting that aging may also lead to a delay or dysfunction in the initial triggering and priming stages of the immune response54,55”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [54]
Most patients with severe COVID-19 have substantially elevated serum levels of proinflammatory cytokines and chemokines, which contribute to pneumonia, cytokine storm, ARDS, sepsis and coagulopathy.
“The majority of patients with severe COVID-19 demonstrate substantially elevated serum levels of proinflammatory cytokines and chemokines, including IL-6, IL-1β, IL-2, IL-8, IL-17, G-CSF, GM-CSF, CXCL10, CCL2, CCL3 and TNF49,54,68.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [54]
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- Authors
- Dinnon, K. H., Leist, S. R., Schäfer, A., Edwards, C. E., Martinez, D. R., Montgomery, S. A., West, A., Yount, B. L., Hou, Y. J., Adams, L. E., Gully, K. L., Brown, A. J., Huang, E., Bryant, M. D., Choong, I. C., Glenn, J. S., Gralinski, L. E., Sheahan, T. P., & Baric, R. S.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Eiger Biopharmaceuticals (United States) (US)
- Palo Alto Veterans Institute for Research (US)
- Corresponding author
- Baric, Ralph S.
- ORCID
- Venue
- Nature
- Published
- 2020-08-27
- Volume
- 586
- Issue
- 7830
- Pages
- 560-566
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC8034761
- OpenAlex
- W3081073771
- Cited by
- 675
- References
- 7
- Citations by year
- 2026: 25 · 2025: 37 · 2024: 80 · 2023: 83 · 2022: 138 · 2021: 224 · 2020: 86 · 2019: 1
- FWCI
- 17.42
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-01-19)
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- PubMed Central (submittedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- UNC Libraries
- Funders
- U.S. Department of Agriculture
- North Carolina General Assembly
- National Institutes of Health (5r01ai132178-05, HHSN272201700036I, DK065988, 5R01AI132178, AI142759)
- University of North Carolina at Chapel Hill
- National Cancer Institute (P30CA016086)
- National Institute of Allergy and Infectious Diseases (R01AI157155, R01-AI132178, AI142759, AI-007419, U19AI100625, U19AI142759, HHSN272201700036I, 5R01AI132178, T32AI007419, AI007151, T32AI007151)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK065988)
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Keywords
- SARS-CoV-2, COVID-19 pandemic, mouse-adapted virus, ACE2, spike protein, reverse genetics, age-related diseases, vaccine challenge, interferon lambda, airway epithelial cells, antiviral therapy, small animal models
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