Asthma Associated Cytokines Regulate the Expression of SARS-CoV-2 Receptor ACE2 in the Lung ‎Tissue of Asthmatic Patients

Abstract

Abstract:‎ It is still controversial whether chronic lung inflammation increases the risk for COVID-19. One of the ‎risk factors for acquiring COVID-19 is the level of expression of SARS-CoV-2 entry receptors, ACE2 and ‎TMPRSS2, in lung tissue. It is, however, not clear how lung tissue inflammation affects expression ‎levels of these receptors. We hence aimed to determine the level of SARS-CoV-2 receptors in lung ‎tissue of asthmatic relative to age, gender, and asthma severity, and to investigate the factors ‎regulating that. Therefore, gene expression data sets of well-known asthmatic cohorts (SARP and U-‎BIOPRED) were used to evaluate the association of ACE2 and TMPRSS2 with age, gender of the ‎asthmatic patients, and also the type of the underlying lung tissue inflammatory cytokines. Notably, ‎ACE2 and to less extent TMPRSS2 expression were upregulated in the lung tissue of asthmatics ‎compared to healthy controls. Although a differential expression of ACE2, but not TMPRSS2 was ‎observed relative to age within the moderate and severe asthma groups, our data suggest that age ‎may not be a key regulatory factor of its expression. The type of tissue inflammation, however, ‎associated significantly with ACE2 and TMPRSS2 expression levels following adjusting with age, gender ‎and oral corticosteroids use of the patient. Type I cytokine (IFN-g), IL-8, and IL-19 were associated with ‎increased expression, while Type II cytokines (IL-4 and IL-13) with lower expression of ACE2 in lung ‎tissue (airway epithelium and/or lung biopsies) of moderate and severe asthmatic patients. Of note, ‎IL-19 was associated with ACE2 expression while IL-17 was associated with TMPRSS2 expression in ‎sputum of asthmatic subjects. In vitro treatment of bronchial fibroblasts with IL-17 and IL-19 cytokines ‎confirmed the regulatory effect of these cytokines on SARS-CoV-2 entry receptors. Our results ‎suggest that the type of inflammation may regulate ACE2 and TMPRSS2 expression in the lung tissue ‎of asthmatics and may hence affect susceptibility to SARS-CoV-2 infection.‎