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SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function
Open accessAbstract
Although animal models have been evaluated for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, none have fully recapitulated the lung disease phenotypes seen in humans who have been hospitalized. Here, we evaluate transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor driven by the cytokeratin-18 (K18) gene promoter (K18-hACE2) as a model of SARS-CoV-2 infection. Intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice results in high levels of viral infection in lungs, with spread to other organs. A decline in pulmonary function occurs 4 days after peak viral titer and correlates with infiltration of monocytes, neutrophils and activated T cells. SARS-CoV-2-infected lung tissues show a massively upregulated innate immune response with signatures of nuclear factor-κB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18-hACE2 model of SARS-CoV-2 infection shares many features of severe COVID-19 infection and can be used to define the basis of lung disease and test immune and antiviral-based countermeasures.
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“In a humanized transgenic mouse model, ACE2 was expressed in the heart and virus replication detected, but they did not observe cardiac inflammation. 181”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [181]
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“These transgenic mice have a human ACE2 receptor which is the major cell entry receptor for SARS-CoV-216,17.”
From Efficacy of an unmodified bivalent mRNA vaccine against SARS-CoV-2 variants in female small animal models (2023) · cites this paper as [17]
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Metadata
- Authors
- Winkler, E. S., Bailey, A. L., Kafai, N. M., Nair, S., McCune, B. T., Yu, J., Fox, J. M., Chen, R. E., Earnest, J. T., Keeler, S. P., Ritter, J. H., Kang, L.-I., Dort, S., Robichaud, A., Head, R., Holtzman, M. J., & Diamond, M. S.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Diamond, Michael S.
- ORCID
- Venue
- Nature Immunology
- Published
- 2020-08-24
- Volume
- 21
- Issue
- 11
- Pages
- 1327-1335
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC7578095
- OpenAlex
- W3080378920
- Cited by
- 901
- References
- 56
- Citations by year
- 2026: 55 · 2025: 72 · 2024: 124 · 2023: 131 · 2022: 234 · 2021: 252 · 2020: 32
- FWCI
- 21.20
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-09-02)
- Open access
- bronze
- doi.org
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (75N93019C00062, R01 AI127828, R01 AI130591, R35 HL145242, F32 AI138392)
- United States Department of Defense | Defense Advanced Research Projects Agency (HR001117S0019)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- SARS-CoV-2, COVID-19 pandemic, K18-hACE2 mice, animal model of COVID-19, lung inflammation, lung function decline, monocytes, neutrophils, T cell activation, innate immune response, interferon signaling, NF-κB signaling
- MeSH terms
- Betacoronavirus, Angiotensin-Converting Enzyme 2, COVID-19, SARS-CoV-2, Animals, Chlorocebus aethiops, Disease Models, Animal, Female, Humans, Immunity, Innate, Interferon Type I, Interferon-gamma, Peptidyl-Dipeptidase A, Leukocytes, Lymphocyte Activation, Male, Mice, Transgenic, Monocytes, Neutrophils, Pneumonia, Pneumonia, Viral, Promoter Regions, Genetic, T-Lymphocytes, Vero Cells, Virus Replication, NF-kappa B, Coronavirus Infections, Neutrophil Infiltration, Mice, Keratin-18, Pandemics
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