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American journal of respiratory cell and molecular biology
01, 2021;64 (1): 79-88.

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

Kun Han, Robert V Blair, Naoki Iwanaga, Fengming Liu, Kasi E Russell-Lodrigue, Zhongnan Qin, Cecily C Midkiff, Nadia A Golden, Lara A Doyle-Meyers, Mohammad E Kabir, Kristin E Chandler, Kellie L Cutrera, Mi Ren, Christopher J Monjure, Gabrielle Lehmicke, Tracy Fischer, Brandon Beddingfield, Alanna G Wanek, Angela Birnbaum, Nicholas J Maness, Chad J Roy, Prasun K Datta, Jay Rappaport, Jay K Kolls, Xuebin Qin
Author Information
  1. Kun Han: Tulane National Primate Research Center, Covington, Louisiana; and.
  2. Robert V Blair: Tulane National Primate Research Center, Covington, Louisiana; and.
  3. Naoki Iwanaga: Department of Medicine and Department of Pediatrics, Center for Translational Research in Infection and Inflammation, and.
  4. Fengming Liu: Tulane National Primate Research Center, Covington, Louisiana; and.
  5. Kasi E Russell-Lodrigue: Tulane National Primate Research Center, Covington, Louisiana; and.
  6. Zhongnan Qin: Tulane National Primate Research Center, Covington, Louisiana; and.
  7. Cecily C Midkiff: Tulane National Primate Research Center, Covington, Louisiana; and.
  8. Nadia A Golden: Tulane National Primate Research Center, Covington, Louisiana; and.
  9. Lara A Doyle-Meyers: Tulane National Primate Research Center, Covington, Louisiana; and.
  10. Mohammad E Kabir: Tulane National Primate Research Center, Covington, Louisiana; and.
  11. Kristin E Chandler: Tulane National Primate Research Center, Covington, Louisiana; and.
  12. Kellie L Cutrera: Tulane National Primate Research Center, Covington, Louisiana; and.
  13. Mi Ren: Tulane National Primate Research Center, Covington, Louisiana; and.
  14. Christopher J Monjure: Tulane National Primate Research Center, Covington, Louisiana; and.
  15. Gabrielle Lehmicke: Tulane National Primate Research Center, Covington, Louisiana; and.
  16. Tracy Fischer: Tulane National Primate Research Center, Covington, Louisiana; and.
  17. Brandon Beddingfield: Tulane National Primate Research Center, Covington, Louisiana; and. ORCID
  18. Alanna G Wanek: Department of Medicine and Department of Pediatrics, Center for Translational Research in Infection and Inflammation, and.
  19. Angela Birnbaum: Tulane National Primate Research Center, Covington, Louisiana; and.
  20. Nicholas J Maness: Tulane National Primate Research Center, Covington, Louisiana; and. ORCID
  21. Chad J Roy: Tulane National Primate Research Center, Covington, Louisiana; and. ORCID
  22. Prasun K Datta: Tulane National Primate Research Center, Covington, Louisiana; and.
  23. Jay Rappaport: Tulane National Primate Research Center, Covington, Louisiana; and.
  24. Jay K Kolls: Department of Medicine and Department of Pediatrics, Center for Translational Research in Infection and Inflammation, and.
  25. Xuebin Qin: Tulane National Primate Research Center, Covington, Louisiana; and. ORCID
PMID: 32991819 DOI: 10.1165/rcmb.2020-0354OC

Abstract

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 and , and genes associated with effector T-cell populations including C. 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.

Keywords

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

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Grants

  1. R35 HL139930/NHLBI NIH HHS
  2. R01 HL141132/NHLBI NIH HHS
  3. P51 OD011104/NIH HHS
  4. P20 GM103629/NIGMS NIH HHS
  5. R01 HL130233/NHLBI NIH HHS
  6. R21 OD024931/NIH HHS

MeSH Term

Adenoviridae
Alveolar Epithelial Cells
Angiotensin-Converting Enzyme 2
Animals
COVID-19
Cytokines
Disease Models, Animal
Gene Expression
Humans
Mice
Mice, Transgenic
SARS-CoV-2
Signal Transduction
Transduction, Genetic

Chemicals

Cytokines
ACE2 protein, human
Angiotensin-Converting Enzyme 2
Journal Article Research Support, N.I.H., Extramural

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