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

• Published in: Nature immunology Vol. 21; no. 11; pp. 1327 - 1335
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2020; Nature Publishing Group
• Subjects: 631/250/2499; 631/326/596/4130; ACE2; Angiotensin; Angiotensin converting enzyme; Angiotensin I; Angiotensin-Converting Enzyme 2; Animal models; Animals; Antiviral drugs; Betacoronavirus - immunology; Biomedical and Life Sciences; Biomedicine; Care and treatment; Cell activation; Chlorocebus aethiops; Coronavirus Infections - immunology; Coronavirus Infections - pathology; Coronaviruses; COVID-19; Cytokeratin; Development and progression; Disease Models, Animal; Female; Gene expression; Genetic aspects; Health aspects; Humans; Immune response; Immunity, Innate - immunology; Immunology; Infections; Infectious Diseases; Inflammation; Innate immunity; Inoculation; Interferon; Interferon Type I - immunology; Interferon-gamma - immunology; Keratin-18 - genetics; Leukocytes (neutrophilic); Leukocytes - immunology; Lung diseases; Lymphocyte Activation - immunology; Lymphocytes T; Male; Mice; Mice, Transgenic; Monocytes; Monocytes - immunology; Neutrophil Infiltration - immunology; Neutrophils - immunology; NF-kappa B - immunology; Pandemics; Peptidyl-dipeptidase A; Peptidyl-Dipeptidase A - genetics; Phenotypes; Pneumonia - genetics; Pneumonia - pathology; Pneumonia - virology; Pneumonia, Viral - immunology; Pneumonia, Viral - pathology; Promoter Regions, Genetic - genetics; Respiratory function; Respiratory tract infections; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; T-Lymphocytes - immunology; Transgenic animals; Transgenic mice; Vero Cells; Viral infections; Virus Replication - immunology; United States
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/s41590-020-0778-2

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. Diamond and colleagues generate a K18-hACE2 model of SARS-CoV-2 infection that 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.