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

2020; Nature Portfolio; Volume: 21; Issue: 11 Linguagem: Inglês

10.1038/s41590-020-0778-2

1529-2916

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

Phagocytosis and Immune Regulation

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.