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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Result
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“This study and our previous work [25] shows that 2×10 4 p.f.u. of SARS-CoV-2 strain WA01/2020 causes severe and lethal disease in K18-hACE2 mice and this is consistent with other studies [28].”
The Fight Against Severe COVID-19: Can Parasitic Worms Contribute?
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Animal models for studying COVID-19, prevention, and therapy: Pathology and disease phenotypes
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Mapping of functional SARS-CoV-2 receptors in human lungs establishes differences in variant binding and SLC1A5 as a viral entry modulator of hACE2
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“13 Based on these studies, the level of expression of hACE2 is an important factor in predicting the SARS-CoV-2 infection.”
Induction of Superior Systemic and Mucosal Protective Immunity to SARS-CoV-2 by Nasal Administration of a VSV–ΔG–Spike Vaccine
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SARS-CoV-2 Ferritin Nanoparticle Vaccines Elicit Broad SARS Coronavirus ImmunogenicityPreprint
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Self-citation
Nucleocapsid-specific humoral responses improve the control of SARS-CoV-2Preprint
Dangi, T., Sanchez, S., Park, M.-C., Class, J., Richner, M., Richner, J. M., & Penaloza‐MacMaster, P. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.03.09.483635 · Cited by 9
SARS-CoV-2 Infects Peripheral and Central Neurons Before Viremia, Facilitated by Neuropilin-1Preprint
Joyce, J. D., Moore, G. A., Goswami, P., Harrell, T. L., Taylor, T. M., Hawks, S. A., Green, J. C., Jia, M., Yallayi, N., Leslie, E. H., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.05.20.492834 · Cited by 9
Development of SARS-CoV-2 mRNA vaccines encoding spike N-terminal and receptor binding domainsPreprint
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Self-citation
Isolation and characterization of an orthoreovirus from Indonesian fruit bats
Intaruck, K., Itakura, Y., Kishimoto, M., Chambaro, H. M., Setiyono, A., Handharyani, E., Uemura, K., Harima, H., Taniguchi, S., Saijo, M., et al. (2022) · Virology · doi:10.1016/j.virol.2022.08.003 · Cited by 8
De Novo Human Angiotensin-Converting Enzyme 2 Decoy NL-CVX1 Protects Mice From Severe Disease After Severe Acute Respiratory Syndrome Coronavirus 2 Infection
Rebelo, M. J. F., Tang, C., Coelho, A. R., Labão‐Almeida, C., Schneider, M. M., Tatalick, L., Ruivo, P., de Miranda, M. P., Gomes, A., Carvalho, T., et al. (2023) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiad135 · Cited by 7
“The inoculum of approximately 1 × 10(4) PFUs was chosen based on published literature [9].”
BackgroundMethod
Berbamine prevents SARS-CoV-2 entry and transmission
Sadhu, S., Goswami, S., Khatri, R., Lohiya, B., Singh, V., Yadav, R., Das, V., Tripathy, M. R., Dwivedi, P., Srivastava, M., et al. (2024) · iScience · doi:10.1016/j.isci.2024.111347 · Cited by 8
Animal Models of Non-Respiratory, Post-Acute Sequelae of COVID-19
Vanderheiden, A., & Diamond, M. (2025) · Viruses · doi:10.3390/v17010098 · Cited by 9
“After intranasal inoculation of transgenic K18-hACE2 mice with SARS-CoV-2, low levels of viral RNA were measured in the intestine along with an altered microbiome at 2 to 6 days post-infection [22,71,101].”
Self-citation
Translating animal models of SARS-CoV-2 infection to vascular, neurological and gastrointestinal manifestations of COVID-19
Chung, J., Pierce, J., Franklin, C. L., Olson, R. M., Morrison, A., & Amos-Landgraf, J. M. (2025) · Disease Models & Mechanisms · doi:10.1242/dmm.052086 · Cited by 9
BSL2-compliant lethal mouse model of SARS-CoV-2 and variants of concern to evaluate therapeutics targeting the Spike protein
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Diabetic Pneumopathy- A Novel Diabetes-associated Complication: Pathophysiology, the Underlying Mechanism and Combination Medication
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Neuropathological lesions in intravenous BCG-stimulated K18-hACE2 mice challenged with SARS-CoV-2
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“In fact, some limitations of this animal model are the risk of ectopic hACE2 expression which changes the cellular tropism of the virus, as well as non-physiological levels of hACE2 expression [46].”
Background
Infiltrating monocytes drive cardiac dysfunction in a cardiomyocyte-restricted mouse model of SARS-CoV-2 infection
Dmytrenko, O., Das, S., Kovács, A. D., Cicka, M., Liu, M., Scheaffer, S. M., Bredemeyer, A. L., Mack, M., Diamond, M., & Lavine, K. J. (2024) · Journal of Virology · doi:10.1128/jvi.01179-24 · Cited by 8
“…control (hereafter, control) and Cre-positive experimental animals (hereafter, hACE2-KI) were intravenously inoculated with 10 6 FFU of WA1/2020, a historical SARS-CoV-2 strain that lacks a mouse-adapting N501Y mutation and only infects cells expressing human and not murine ACE2 (29, 38).”
Self-citation
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Cleary, S. J., Magnen, M., Looney, M. R., & Page, C. P. (2020) · British Journal of Pharmacology · doi:10.1111/bph.15266 · Cited by 8
Modeling SARS-CoV-2 infection in individuals with opioid use disorder with brain organoids
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Natural and genetically-modified animal models to investigate pulmonary and extrapulmonary manifestations of COVID-19
Tiwari, S., Goel, G., & Kumar, A. (2022) · International Reviews of Immunology · doi:10.1080/08830185.2022.2089666 · Cited by 9
“Firstly, Winkler et al., 2020 found that the K18-hACE2 Tg mouse model exhibited severe clinical manifestations of COVID-19 infection and showed that these models could be used to understand the pathophysiology of COVID-19, ARDS, and screening of antiviral drugs [23].”
BackgroundInfluential
Dok3 restrains neutrophil production of calprotectin during TLR4 sensing of SARS-CoV-2 spike protein
Loh, J. T., Teo, J. K. H., & Lam, K. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.996637 · Cited by 9
A minimally-edited mouse model for infection with multiple SARS-CoV-2 strains
Nakandakari-Higa, S., Parsa, R., Reis, B. S., de Carvalho, R. A., Mesin, L., Hoffmann, H.-H., Bortolatto, J., Muramatsu, H., Lin, P. J. C., Bilate, A. M. B., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1007080 · Cited by 8
A Selective SARS-CoV-2 Host-Directed Antiviral Targeting Stress Response to Reactive Oxygen Species
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Animal Models for the Study of Neurologic Manifestations Of COVID-19
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Vectored immunoprophylaxis and treatment of SARS-CoV-2 infection in a preclinical model
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Preclinical immune efficacy against SARS-CoV-2 beta B.1.351 variant by MVA-based vaccine candidates
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Topoisomerase 1 inhibition therapy protects against SARS-CoV-2-induced inflammation and death in animal modelsPreprint
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“As such, K18-hACE2 have been suggested as a model to define the basis of SARS-CoV-2-induced lung disease and test immune and antiviral countermeasures (Bao et al., 2020; Winkler et al., 2020).”
Background
Isolation and Characterization of Cross-Neutralizing Coronavirus Antibodies from COVID-19+ SubjectsPreprint
Jennewein, M. F., MacCamy, A. J., Akins, N. R., Feng, J., Homad, L. J., Hurlburt, N. K., Seydoux, E., Wan, Y.-H., Stuart, A. B., Edara, V. V., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.03.23.436684 · Cited by 9
Mosaic RBD nanoparticles protect against multiple sarbecovirus challenges in animal modelsPreprint
Cohen, A. A., van Doremalen, N., Greaney, A. J., Andersen, H., Sharma, A., Starr, T. N., Keeffe, J., Fan, C.-H., Schulz, J. E., Gnanapragasam, P. N. P., et al. (2022) · bioRxiv · doi:10.1101/2022.03.25.485875 · Cited by 5
Characterization of Collaborative Cross mouse founder strain CAST/EiJ as a novel model for lethal COVID-19
Baker, C. N., Duso, D. K., Kothapalli, N. R., Hart, T., Casey, S., Cookenham, T. S., Kummer, L. W., Hvizdos, J., Lanzer, K. G., Vats, P., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-77087-1 · Cited by 7
“As previously reported, K18-hACE2 mice began to show weight loss starting 2–3 days post infection (dpi) and continued to lose weight until they reached humane endpoints (loss of > 25% of their pre-infection body weight or being found moribund) at day 5 to 7 post-infection 17,21 .”
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Xu, R., Hong, H. A., Khandaker, S., Baltazar, M., Allehyani, N., Beentjes, D., Prince, T., Ho, Y.-L. T., Nguyen, L. H., Hynes, D., et al. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1501907 · Cited by 10
Phellinus linteus mycelia extract in COVID-19 prevention and identification of its key metabolic compounds profiling using UPLC-QTOF-MS/MS spectrometry
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AG5 is a potent non-steroidal anti-inflammatory and immune regulator that preserves innate immunity
Asunción, P. B., Rivero-Buceta, E. M., Vidaurre-Agut, C., Lama, R., Rey-Campos, M., Moreno, A., Mendoza, L., Mingo‐Casas, P., Escribano-Romero, E., Gutiérrez‐Adán, A., et al. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115882 · Cited by 7
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Selective phosphodiesterase 4 inhibitor roflumilast reduces inflammation and lung injury in models of betacoronavirus infection in mice
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“Additionally, transgenic mice expressing the human angiotensin I-con-verting enzyme 2 (ACE2) receptor, driven by the cytokeratin-18 (K18) gene promoter (K18-hACE2), are susceptible to intranasal SARS-CoV-2 infection, which results in severe lung inflammation and impaired function [ 17].”
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Gantier, M. P. (2020) · Respirology · doi:10.1111/resp.13997 · Cited by 7
Pharmacotherapeutics of SARS-CoV-2 Infections
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Murine Models of Chronic Viral Infections and Associated Cancers
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Soluble Angiotensin-Converting Enzyme 2 Protein Improves Survival and Lowers Viral Titers in Lethal Mouse Model of Severe Acute Respiratory Syndrome Coronavirus Type 2 Infection with the Delta Variant
Cianfarini, C. L., Hassler, L., Wysocki, J. A., Hassan, A., Nicolaescu, V. I., Elli, D., Gula, H., Ibrahim, A. M., Randall, G. C., Henkin, J., et al. (2024) · Cells · doi:10.3390/cells13030203 · Cited by 7
“Disease severity in k18-hACE2 mice infected with the SARS-CoV-2 Delta variant has been reported to be similar to or greater than infection with the ancestral virus, where animals typically succumb to disease by days 5–9 post-viral inoculation [22,23,33–36,”
BackgroundMethod
Tracking inflammation resolution signatures in lungs after SARS-CoV-2 omicron BA.1 infection of K18-hACE2 mice
Carolin, A., Yan, K., Bishop, C., Tang, B., Nguyen, W., Rawle, D. J., & Suhrbier, A. (2024) · PLoS ONE · doi:10.1371/journal.pone.0302344 · Cited by 9
“Few differentially expressed genes (DEGs) were identified in lungs by 66 dpi, arguing that the model describes near complete resolution of the infection, without long-term pulmonary sequelae.”
Influential

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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