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Influenza virus infection increases ACE2 expression and shedding in human small airway epithelial cells

Kelly S. Schweitzer, Taylor Crue, Jordan M. Nall, Daniel Foster, Satria Sajuthi, Kelly A. Correll, Mari Nakamura, Jamie Everman, Gregory P. Downey, Max A. Seibold, James P. Bridges, Karina A. Serban, Hong Wei Chu, Irina Petrache
European Respiratory Journal 2021; DOI: 10.1183/13993003.03988-2020
Kelly S. Schweitzer
1Department of Medicine, National Jewish Health, Denver, CO, USA
2Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA
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Taylor Crue
1Department of Medicine, National Jewish Health, Denver, CO, USA
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Jordan M. Nall
1Department of Medicine, National Jewish Health, Denver, CO, USA
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Daniel Foster
1Department of Medicine, National Jewish Health, Denver, CO, USA
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Satria Sajuthi
3Department of Pediatrics, National Jewish Health, Denver, CO, USA
4Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA
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  • ORCID record for Satria Sajuthi
Kelly A. Correll
1Department of Medicine, National Jewish Health, Denver, CO, USA
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Mari Nakamura
1Department of Medicine, National Jewish Health, Denver, CO, USA
2Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA
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Jamie Everman
3Department of Pediatrics, National Jewish Health, Denver, CO, USA
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  • ORCID record for Jamie Everman
Gregory P. Downey
1Department of Medicine, National Jewish Health, Denver, CO, USA
2Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA
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Max A. Seibold
3Department of Pediatrics, National Jewish Health, Denver, CO, USA
4Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA
2Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA
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  • ORCID record for Max A. Seibold
James P. Bridges
1Department of Medicine, National Jewish Health, Denver, CO, USA
2Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA
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Karina A. Serban
1Department of Medicine, National Jewish Health, Denver, CO, USA
2Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA
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Hong Wei Chu
1Department of Medicine, National Jewish Health, Denver, CO, USA
2Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA
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Irina Petrache
1Department of Medicine, National Jewish Health, Denver, CO, USA
2Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA
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  • For correspondence: PetracheI@NJHealth.org chuhw@njhealth.org
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Abstract

Patients with COVID-19 caused by severe acute respiratory syndrome coronavirus (SARS-Co-V)-2 demonstrate high rates of co-infection with respiratory viruses, including influenza A (IAV), suggesting pathogenic interactions. We investigated how IAV may increase the risk for COVID-19 lung disease, focusing on the receptor Angiotensin Convertase Enzyme 2 (ACE2) and the protease TMPRSS2, which cooperate to uptake SARS-CoV-2 intracellular. We found, using single cell RNA sequencing of distal human non-diseased lung homogenates, that at baseline, ACE2 is minimally expressed in basal, goblet, ciliated, and secretory epithelial cells populating small airways. We focused on human small airway epithelial cells (SAEC), central to the pathogenesis of lung injury following viral infections. Primary SAEC from non-diseased donor lungs apically infected (at air-liquid interface) with IAV (up to 3×105 pfu; ∼1 MOI) markedly (8-fold) boosted the expression of ACE2, paralleling that of STAT1, a transcription factor activated by viruses. IAV increased the apparent electrophoretic mobility of intrac¬ellular ACE2 and generated an ACE2 fragment (90 kDa) in apical secretions, suggesting cleavage of this receptor. IAV also increased the expression of two proteases known to cleave ACE2, sheddase ADAM17 (TACE) and TMPRSS2 and increased the TMPRSS2 zymogen and its mature fragments, implicating proteolytic autoactivation. These results indicate that IAV amplifies the expression of molecules necessary for SARS-CoV-2 infection of the distal lung. Further, posttranslational changes in ACE2 by IAV may increase the vulnerability to lung injury such as ARDS during viral co-infections. These findings support prevention and treatment efforts of influenza infections during the COVID-19 pandemic.

Footnotes

This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.

Conflict of interest: Dr. Schweitzer has nothing to disclose.

Conflict of interest: Ms. Crue has nothing to disclose.

Conflict of interest: Dr. Nall has nothing to disclose.

Conflict of interest: Mr. Foster has nothing to disclose.

Conflict of interest: Dr. Sajuthi has nothing to disclose.

Conflict of interest: Ms. Correll has nothing to disclose.

Conflict of interest: Dr. Nakamura has nothing to disclose.

Conflict of interest: I, Jamie Everman, have nothing to disclose.

Conflict of interest: Dr. Downey has nothing to disclose.

Conflict of interest: Dr. Seibold reports grants from NIH, during the conduct of the study;.

Conflict of interest: Dr. Bridges has nothing to disclose.

Conflict of interest: Dr. Serban has nothing to disclose.

Conflict of interest: Dr. Chu has nothing to disclose.

Conflict of interest: Dr. Petrache has nothing to disclose.

  • Received October 28, 2020.
  • Accepted November 30, 2020.
  • Copyright ©ERS 2021
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Influenza virus infection increases ACE2 expression and shedding in human small airway epithelial cells
Kelly S. Schweitzer, Taylor Crue, Jordan M. Nall, Daniel Foster, Satria Sajuthi, Kelly A. Correll, Mari Nakamura, Jamie Everman, Gregory P. Downey, Max A. Seibold, James P. Bridges, Karina A. Serban, Hong Wei Chu, Irina Petrache
European Respiratory Journal Jan 2021, 2003988; DOI: 10.1183/13993003.03988-2020

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Influenza virus infection increases ACE2 expression and shedding in human small airway epithelial cells
Kelly S. Schweitzer, Taylor Crue, Jordan M. Nall, Daniel Foster, Satria Sajuthi, Kelly A. Correll, Mari Nakamura, Jamie Everman, Gregory P. Downey, Max A. Seibold, James P. Bridges, Karina A. Serban, Hong Wei Chu, Irina Petrache
European Respiratory Journal Jan 2021, 2003988; DOI: 10.1183/13993003.03988-2020
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