tetano
Editor, Senior Moderator
Nat Immunol
. 2020 Aug 24.
doi: 10.1038/s41590-020-0778-2. Online ahead of print.
SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function
Emma S Winkler[SUP] 1 2 [/SUP], Adam L Bailey[SUP] 2 [/SUP], Natasha M Kafai[SUP] 1 2 [/SUP], Sharmila Nair[SUP] 1 [/SUP], Broc T McCune[SUP] 1 [/SUP], Jinsheng Yu[SUP] 3 [/SUP], Julie M Fox[SUP] 1 [/SUP], Rita E Chen[SUP] 1 2 [/SUP], James T Earnest[SUP] 1 [/SUP], Shamus P Keeler[SUP] 1 4 [/SUP], Jon H Ritter[SUP] 2 [/SUP], Liang-I Kang[SUP] 2 [/SUP], Sarah Dort[SUP] 5 [/SUP], Annette Robichaud[SUP] 5 [/SUP], Richard Head[SUP] 3 [/SUP], Michael J Holtzman[SUP] 1 4 [/SUP], Michael S Diamond[SUP] 6 7 8 9 [/SUP]
Affiliations
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.
. 2020 Aug 24.
doi: 10.1038/s41590-020-0778-2. Online ahead of print.
SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function
Emma S Winkler[SUP] 1 2 [/SUP], Adam L Bailey[SUP] 2 [/SUP], Natasha M Kafai[SUP] 1 2 [/SUP], Sharmila Nair[SUP] 1 [/SUP], Broc T McCune[SUP] 1 [/SUP], Jinsheng Yu[SUP] 3 [/SUP], Julie M Fox[SUP] 1 [/SUP], Rita E Chen[SUP] 1 2 [/SUP], James T Earnest[SUP] 1 [/SUP], Shamus P Keeler[SUP] 1 4 [/SUP], Jon H Ritter[SUP] 2 [/SUP], Liang-I Kang[SUP] 2 [/SUP], Sarah Dort[SUP] 5 [/SUP], Annette Robichaud[SUP] 5 [/SUP], Richard Head[SUP] 3 [/SUP], Michael J Holtzman[SUP] 1 4 [/SUP], Michael S Diamond[SUP] 6 7 8 9 [/SUP]
Affiliations
- PMID: 32839612
- DOI: 10.1038/s41590-020-0778-2
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.