Cited by 906SARS-CoV-2 and COVID-19 ResearchCOVID-19 Clinical Research Studiesinterferon and immune responses

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SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function

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Winkler, Emma S., Bailey, Adam L., Kafai, Natasha M., Nair, Sharmila, McCune, Broc T., Yu, Jinsheng, Fox, Julie M., Chen, Rita E., Earnest, James T., Keeler, Shamus P., Ritter, Jon H., Kang, Liang-I, Dort, Sarah, Robichaud, Annette, Head, Richard, Holtzman, Michael J., Diamond, Michael S.·2020·Nature Immunology

DOI 10.1038/s41590-020-0778-2PMC PMC7578095

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Abstract

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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Additional file 6 of Neuropathological lesions in intravenous BCG-stimulated K18-hACE2 mice challenged with SARS-CoV-2
Sánchez‐Morales, L., Porras, N., García‐Seco, T., Sancho, M. P., Cruz, F., Chinchilla, B., Barroso‐Arévalo, S., Díaz-Frutos, M., Buendía, A., Moreno, I., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26728360
Additional file 3 of Effective protection of ZF2001 against the SARS-CoV-2 Delta variant in lethal K18-hACE2 mice
Bian, L., Bai, Y., Gao, F., Liu, M., He, Q., Wu, X., Mao, Q., Xu, M., & 梁争论 (2022) · Figshare · doi:10.6084/m9.figshare.19807954
Additional file 2 of Effective protection of ZF2001 against the SARS-CoV-2 Delta variant in lethal K18-hACE2 mice
Bian, L., Bai, Y., Gao, F., Liu, M., He, Q., Wu, X., Mao, Q., Xu, M., & 梁争论 (2022) · Figshare · doi:10.6084/m9.figshare.19807951
Additional file 5 of Neuropathological lesions in intravenous BCG-stimulated K18-hACE2 mice challenged with SARS-CoV-2
Sánchez‐Morales, L., Porras, N., García‐Seco, T., Sancho, M. P., Cruz, F., Chinchilla, B., Barroso-Arévalo, S., Díaz-Frutos, M., Buendía, A., Moreno, I., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26728357
Additional file 2 of Neuropathological lesions in intravenous BCG-stimulated K18-hACE2 mice challenged with SARS-CoV-2
Sánchez‐Morales, L., Porras, N., García‐Seco, T., Sancho, M. P., Cruz, F., Chinchilla, B., Barroso-Arévalo, S., Díaz-Frutos, M., Buendía, A., Moreno, I., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26728345
Additional file 1 of Neuropathological lesions in intravenous BCG-stimulated K18-hACE2 mice challenged with SARS-CoV-2
Sánchez‐Morales, L., Porras, N., García‐Seco, T., Sancho, M. P., Cruz, F., Chinchilla, B., Barroso-Arévalo, S., Díaz-Frutos, M., Buendía, A., Moreno, I., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26728342
Additional file 1 of Effective protection of ZF2001 against the SARS-CoV-2 Delta variant in lethal K18-hACE2 mice
Bian, L., Bai, Y., Gao, F., Liu, M., He, Q., Wu, X., Mao, Q., Xu, M., & 梁争论 (2022) · Figshare · doi:10.6084/m9.figshare.19807948
Additional file 3 of Neuropathological lesions in intravenous BCG-stimulated K18-hACE2 mice challenged with SARS-CoV-2
Sánchez‐Morales, L., Porras, N., García‐Seco, T., Sancho, M. P., Cruz, F., Chinchilla, B., Barroso-Arévalo, S., Díaz-Frutos, M., Buendía, A., Moreno, I., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26728348
Additional file 4 of Neuropathological lesions in intravenous BCG-stimulated K18-hACE2 mice challenged with SARS-CoV-2
Sánchez‐Morales, L., Porras, N., García‐Seco, T., Sancho, M. P., Cruz, F., Chinchilla, B., Barroso-Arévalo, S., Díaz-Frutos, M., Buendía, A., Moreno, I., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26728354
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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: Winkler, Emma S.
Bailey, Adam L.
Kafai, Natasha M.
Nair, Sharmila
McCune, Broc T.
Yu, Jinsheng
Fox, Julie M.
Chen, Rita E.
Earnest, James T.
Keeler, Shamus P.
Ritter, Jon H.
Kang, Liang-I
Head, Richard
Holtzman, Michael J.
Diamond, Michael S.
Venue: Nature Immunology
Publisher: Springer Science and Business Media LLC
Published: 2020-08-24
Volume: 21
Issue: 11
Pages: 1327-1335
ISSN: 1529-2908 (ISSN-L)
1529-2916
DOI: 10.1038/s41590-020-0778-2
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
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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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SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function

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