SARS-CoV-2 infection of hACE2 transgenic mice causes severe lung inflammation and impaired function

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.

Although animal models have been evaluated for Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection, none have fully recapitulated the severe lung disease phenotypes seen in hospitalized human cases. Here, we evaluate transgenic mice expressing the human ACE2 receptor driven by the cytokeratin-18 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 NF-kB-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.