Abstract
Background Patients with coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) demonstrate high rates of co-infection with respiratory viruses, including influenza A (IAV), suggesting pathogenic interactions.
Methods We investigated how IAV may increase the risk of COVID-19 lung disease, focusing on the receptor angiotensin-converting enzyme (ACE)2 and the protease TMPRSS2, which cooperate in the intracellular uptake of SARS-CoV-2.
Results We found, using single-cell RNA sequencing of distal human nondiseased 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 (SAECs), central to the pathogenesis of lung injury following viral infections. Primary SAECs from nondiseased donor lungs apically infected (at the air–liquid interface) with IAV (up to 3×105 pfu; ∼1 multiplicity of infection) markedly (eight-fold) boosted the expression of ACE2, paralleling that of STAT1, a transcription factor activated by viruses. IAV increased the apparent electrophoretic mobility of intracellular ACE2 and generated an ACE2 fragment (90 kDa) in apical secretions, suggesting cleavage of this receptor. In addition, IAV 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.
Conclusion These results indicate that IAV amplifies the expression of molecules necessary for SARS-CoV-2 infection of the distal lung. Furthermore, post-translational changes in ACE2 by IAV may increase vulnerability to lung injury such as acute respiratory distress syndrome during viral co-infections. These findings support efforts in the prevention and treatment of influenza infections during the COVID-19 pandemic.
Abstract
Influenza virus infection of cells lining the small airways increases the expression of molecules required for SARS-CoV-2 uptake in a manner that predicts increased severity of lung disease in those co-infected with influenza and coronaviruses https://bit.ly/3nu1WAo
Footnotes
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Author contributions: K.S. Schweitzer performed and designed experiments, and analysed and interpreted data. T. Crue performed experiments and analysed and interpreted data. J.M. Nall performed experiments and analysed data. D. Foster performed experiments and analysed data, prepared manuscript. S. Sajuthi performed experiments and analysed data. K.A. Correll performed experiments. M. Nakamura provided key reagents and designed experiments. J.L. Everman performed experiments and analysed data. G.P. Downey designed experiments, and analysed and interpreted data. M.A. Seibold designed experiments, and analysed and interpreted. J.P. Bridges performed experiments, and analysed and interpreted data. K.A. Serban performed experiments, and analysed and interpreted data. H.W. Chu and I. Petrache designed and coordinated experiments, performed data analysis, interpretation, and wrote the manuscript.
Conflict of interest: K.S. Schweitzer has nothing to disclose.
Conflict of interest: T. Crue has nothing to disclose.
Conflict of interest: J.M. Nall has nothing to disclose.
Conflict of interest: D. Foster has nothing to disclose.
Conflict of interest: S. Sajuthi has nothing to disclose.
Conflict of interest: K.A. Correll has nothing to disclose.
Conflict of interest: M. Nakamura has nothing to disclose.
Conflict of interest: J.L. Everman has nothing to disclose.
Conflict of interest: G.P. Downey has nothing to disclose.
Conflict of interest: M.A. Seibold reports grants from NIH (U01 HL138626, R01 HL135156, R01 MD010443, R01 HL128439, P01 HL132821, P01 HL107202, R01 HL117004), during the conduct of the study.
Conflict of interest: J.P. Bridges has nothing to disclose.
Conflict of interest: K.A. Serban has nothing to disclose.
Conflict of interest: H.W. Chu has nothing to disclose.
Conflict of interest: I. Petrache has nothing to disclose.
Support statement: Research was supported by the American Lung Association (Emerging Respiratory Viruses Research Award) and the National Institutes of Health NHLBI, R01 HL144396 (H.W. Chu and I. Petrache). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received July 14, 2020.
- Accepted November 30, 2020.
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