SARS-CoV-2 Infection of Human ACE2-transgenic Mice Causes Severe Lung Inflammation and Impaired Function

Overview

Journal Nat Immunol

Date 2020 Aug 26

PMID 32839612

Citations 583

Authors

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 Head

Michael J Holtzman

Michael S Diamond

Affiliations

Soon will be listed here.

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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References

Wang L, Wang S, Li W . RSeQC: quality control of RNA-seq experiments. Bioinformatics. 2012; 28(16):2184-5. DOI: 10.1093/bioinformatics/bts356. View

Liao Y, Smyth G, Shi W . featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2013; 30(7):923-30. DOI: 10.1093/bioinformatics/btt656. View

Hassan A, Case J, Winkler E, Thackray L, Kafai N, Bailey A . A SARS-CoV-2 Infection Model in Mice Demonstrates Protection by Neutralizing Antibodies. Cell. 2020; 182(3):744-753.e4. PMC: 7284254. DOI: 10.1016/j.cell.2020.06.011. View

Li Y, Zhou W, Yang L, You R . Physiological and pathological regulation of ACE2, the SARS-CoV-2 receptor. Pharmacol Res. 2020; 157:104833. PMC: 7194807. DOI: 10.1016/j.phrs.2020.104833. View

Fu L, Wang B, Yuan T, Chen X, Ao Y, Fitzpatrick T . Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: A systematic review and meta-analysis. J Infect. 2020; 80(6):656-665. PMC: 7151416. DOI: 10.1016/j.jinf.2020.03.041. View

Robichaud A, Fereydoonzad L, Urovitch I, Brunet J . Comparative study of three flexiVent system configurations using mechanical test loads. Exp Lung Res. 2014; 41(2):84-92. DOI: 10.3109/01902148.2014.971921. View

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y . Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395(10223):497-506. PMC: 7159299. DOI: 10.1016/S0140-6736(20)30183-5. View

Mehta P, McAuley D, Brown M, Sanchez E, Tattersall R, Manson J . COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020; 395(10229):1033-1034. PMC: 7270045. DOI: 10.1016/S0140-6736(20)30628-0. View

Pan F, Ye T, Sun P, Gui S, Liang B, Li L . Time Course of Lung Changes at Chest CT during Recovery from Coronavirus Disease 2019 (COVID-19). Radiology. 2020; 295(3):715-721. PMC: 7233367. DOI: 10.1148/radiol.2020200370. View

10.

Liu R, Holik A, Su S, Jansz N, Chen K, Leong H . Why weight? Modelling sample and observational level variability improves power in RNA-seq analyses. Nucleic Acids Res. 2015; 43(15):e97. PMC: 4551905. DOI: 10.1093/nar/gkv412. View

11.

Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H . Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020; 130(5):2620-2629. PMC: 7190990. DOI: 10.1172/JCI137244. View

12.

Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C . Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020; 8(4):420-422. PMC: 7164771. DOI: 10.1016/S2213-2600(20)30076-X. View

13.

Channappanavar R, Fehr A, Vijay R, Mack M, Zhao J, Meyerholz D . Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice. Cell Host Microbe. 2016; 19(2):181-93. PMC: 4752723. DOI: 10.1016/j.chom.2016.01.007. View

14.

Mostafavi S, Yoshida H, Moodley D, LeBoite H, Rothamel K, Raj T . Parsing the Interferon Transcriptional Network and Its Disease Associations. Cell. 2016; 164(3):564-78. PMC: 4743492. DOI: 10.1016/j.cell.2015.12.032. View

15.

Tan L, Wang Q, Zhang D, Ding J, Huang Q, Tang Y . Correction: Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study. Signal Transduct Target Ther. 2020; 5(1):61. PMC: 7189020. DOI: 10.1038/s41392-020-0159-1. View

16.

Liao M, Liu Y, Yuan J, Wen Y, Xu G, Zhao J . Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19. Nat Med. 2020; 26(6):842-844. DOI: 10.1038/s41591-020-0901-9. View

17.

Spinato G, Fabbris C, Polesel J, Cazzador D, Borsetto D, Hopkins C . Alterations in Smell or Taste in Mildly Symptomatic Outpatients With SARS-CoV-2 Infection. JAMA. 2020; 323(20):2089-2090. PMC: 7177631. DOI: 10.1001/jama.2020.6771. View

18.

Netland J, Meyerholz D, Moore S, Cassell M, Perlman S . Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J Virol. 2008; 82(15):7264-75. PMC: 2493326. DOI: 10.1128/JVI.00737-08. View

19.

Yang Y, Shen C, Li J, Yuan J, Wei J, Huang F . Plasma IP-10 and MCP-3 levels are highly associated with disease severity and predict the progression of COVID-19. J Allergy Clin Immunol. 2020; 146(1):119-127.e4. PMC: 7189843. DOI: 10.1016/j.jaci.2020.04.027. View

20.

BARNETT E, Cassell M, Perlman S . Two neurotropic viruses, herpes simplex virus type 1 and mouse hepatitis virus, spread along different neural pathways from the main olfactory bulb. Neuroscience. 1993; 57(4):1007-25. PMC: 7131965. DOI: 10.1016/0306-4522(93)90045-h. View