Determinants of SARS-CoV-2 receptor gene expression in upper and lower airways

Aliee, H.; Massip, F.; Qi, C.; de Biase, M. Stella; van Nijnatten, J.; Kersten, E.T.G.; Kermani, N. Z.; Khuder, B.; Vonk, J. M; Vermeulen, R.C H; Neighbors, M.; Tew, G. W.; Grimbaldeston, M.; ten Hacken, N. H. T.; Hu, S.; Guo, Y.; Zhang, X.; Sun, K.; Hiemstra, P.S.; Ponder, B.A.; Mäkelä, M. J.; Malmström, K.; Rintoul, R.C; Reyfman, P.A.; Theis, F.J.; Brandsma, C.A.; Adcock, I. M.; Timens, W.; Xu, C.J.; van den Berge, M.; Schwarz, R. F.; Koppelman, G. H.; Nawijn, M.C.; Faiz, A.

BACKGROUND: The recent outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has led to a worldwide pandemic. A subset of COVID-19 patients progresses to severe disease, with high mortality and limited treatment options. Detailed knowledge of the expression regulation of genes required for viral entry into respiratory epithelial cells is urgently needed. METHODS: Here we assess the expression patterns of genes required for SARS-CoV-2 entry into cells, and their regulation by genetic, epigenetic and environmental factors, throughout the respiratory tract using samples collected from the upper (nasal) and lower airways (bronchi). FINDINGS: Genes encoding viral receptors and activating protease are increased in the nose compared to the bronchi in matched samples and associated with the proportion of secretory epithelial cells in cellular deconvolution analyses. Current or ex-smoking was found to increase expression of these genes only in lower airways, which was associated with a significant increase in the predicted proportion of goblet cells. Both acute and second hand smoke exposure were found to increase ACE2 expression while inhaled corticosteroids decrease ACE2 expression in the lower airways. A strong association of DNA- methylation with ACE2 and TMPRSS2- mRNA expression was identified. INTERPRETATION: Genes associated with SARS-CoV-2 viral entry into cells are high in upper airways, but strongly increased in lower airways by smoke exposure. In contrast, ICS decreases ACE2 expression, indicating that inhaled corticosteroids are unlikely to increase the risk for more severe COVID-19 disease.