Influenza virus infection increases ACE2 expression and shedding in human small airway epithelial cells
Year: 2021
Type: article
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.
Source: European Respiratory Journal
Institutions: National Jewish Health, University of Colorado Anschutz
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: Transcriptomic and Pharmacogenetic Asthma Endotypes in Minority Children, The Airway Functional Genomics of Bronchodilator Drug Response in Minority Children with Asthma, Exploring the biology of persistent type 2 airway niches in asthma, Genetic Control of Airway Epithelium Gene Expression in Childhood Asthmatics, G614895205, Defining Molecular Phenotypes of Exacerbation Prone Asthmatics, Immunosuppressive injurious effects of e-cigarettes on human lung parenchyma, Genes, air pollution, and asthma severity in minority children, Checkpoint Function of PTPalpha in Pathological Fibrogenesis in the Lung, Natural History of Viral Induced Airway Dysfunction and Asthma in Minority Children, Innate Immunity and Viral Infection in Asthma, Multi-Disciplinary Research Training in Respiratory Disease, Proteolysis in the Pathogenesis of ARDS
OpenAlex ID: W3119344443