Open AccessLung Expression of Human Angiotensin-Converting Enzyme 2 Sensitizes the Mouse to SARS-CoV-2 Infection
Author(s) -
Kun Han,
Robert V Blair,
Nozomi Iwanaga,
Fengming Liu,
Kasi RussellLodrigue,
Zhongnan Qin,
Cecily C. Midkiff,
Nadia Golden,
Lara DoyleMeyers,
Mohammad E. Kabir,
Kristin Chandler,
Kellie L. Cutrera,
Mengye Ren,
Christopher Monjure,
Gabrielle Lehmicke,
Tracy Fischer,
Brandon J Beddingfield,
Alanna Wanek,
Angela K. Birnbaum,
Nicholas J. Maness,
Chad J. Roy,
Prasun K. Datta,
Jay Rappaport,
Jay K. Kolls,
Xuebin Qin
Publication year - 2021
Publication title -
american journal of respiratory cell and molecular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.469
H-Index - 161
eISSN - 1535-4989
pISSN - 1044-1549
DOI - 10.1165/rcmb.2020-0354oc
Subject(s) - biology , immunology , virology , chemokine , kegg , signal transduction , inflammation , microbiology and biotechnology , transcriptome , gene expression , gene , biochemistry
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.