Lung Expression of Human Angiotensin-Converting Enzyme 2 Sensitizes the Mouse to SARS-CoV-2 Infection.

Publisher: American Thoracic Society Country of Publication: United States NLM ID: 8917225 Publication Model: Print Cited Medium: Internet ISSN: 1535-4989 (Electronic) Linking ISSN: 10441549 NLM ISO Abbreviation: Am J Respir Cell Mol Biol Subsets: MEDLINE

Publication: 2000- : New York, NY : American Thoracic Society
Original Publication: [New York, NY : The Association, [c1989-

Gene Expression*; Alveolar Epithelial Cells/*immunology ; COVID-19/*immunology ; SARS-CoV-2/*immunology ; Signal Transduction/*immunology; Adenoviridae/genetics ; Adenoviridae/metabolism ; Alveolar Epithelial Cells/metabolism ; Alveolar Epithelial Cells/virology ; Angiotensin-Converting Enzyme 2/biosynthesis ; Angiotensin-Converting Enzyme 2/genetics ; Angiotensin-Converting Enzyme 2/immunology ; Animals ; COVID-19/genetics ; COVID-19/metabolism ; COVID-19/pathology ; Cytokines/genetics ; Cytokines/immunology ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; SARS-CoV-2/genetics ; SARS-CoV-2/metabolism ; Signal Transduction/genetics ; Transduction, Genetic

Preclinical mouse models that recapitulate some characteristics of coronavirus disease (COVID-19) will facilitate focused study of pathogenesis and virus-host responses. Human agniotensin-converting enzyme 2 (hACE2) serves as an entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to infect people via binding to envelope spike proteins. Herein we report development and characterization of a rapidly deployable COVID-19 mouse model. C57BL/6J (B6) mice expressing hACE2 in the lung were transduced by oropharyngeal delivery of the recombinant human adenovirus type 5 that expresses hACE2 (Ad5-hACE2). Mice were infected with SARS-CoV-2 at Day 4 after transduction and developed interstitial pneumonia associated with perivascular inflammation, accompanied by significantly higher viral load in lungs at Days 3, 6, and 12 after infection compared with Ad5-empty control group. SARS-CoV-2 was detected in pneumocytes in alveolar septa. Transcriptomic analysis of lungs demonstrated that the infected Ad5-hACE mice had a significant increase in IFN-dependent chemokines Cxcl9 and Cxcl10 , and genes associated with effector T-cell populations including C d3 g, Cd8a, and Gzmb . Pathway analysis showed that several Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were enriched in the data set, including cytokine-cytokine receptor interaction, the chemokine signaling pathway, the NOD-like receptor signaling pathway, the measles pathway, and the IL-17 signaling pathway. This response is correlative to clinical response in lungs of patients with COVID-19. These results demonstrate that expression of hACE2 via adenovirus delivery system sensitized the mouse to SARS-CoV-2 infection and resulted in the development of a mild COVID-19 phenotype, highlighting the immune and inflammatory host responses to SARS-CoV-2 infection. This rapidly deployable COVID-19 mouse model is useful for preclinical and pathogenesis studies of COVID-19.

Comment in: Am J Respir Cell Mol Biol. 2021 Jan;64(1):7-9. (PMID: 33170734)
Erratum in: Am J Respir Cell Mol Biol. 2021 Jul;65(1):121. (PMID: 34241583)

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R35 HL139930 United States HL NHLBI NIH HHS; R01 HL141132 United States HL NHLBI NIH HHS; P51 OD011104 United States OD NIH HHS; P20 GM103629 United States GM NIGMS NIH HHS; R01 HL130233 United States HL NHLBI NIH HHS; R21 OD024931 United States OD NIH HHS

Keywords: COVID-19; SARS-CoV-2; human ACE2; immune responses; mouse model

0 (Cytokines)
EC 3.4.17.23 (ACE2 protein, human)
EC 3.4.17.23 (Angiotensin-Converting Enzyme 2)

Date Created: 20200929 Date Completed: 20210111 Latest Revision: 20240330

20240330

PMC7781002

10.1165/rcmb.2020-0354OC

32991819