Determinants of SARS-CoV-2 receptor gene expression in upper and lower airways
Authors: 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 ,   U-BIOPRED study group,   Cambridge Lung Cancer Early Detection Programme,   INER-Ciencias Mexican Lung Program,   NHLBI LungMAP Consortium, 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. 
Published: September 2020

AbstractBackgroundThe 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.MethodsHere 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).FindingsGenes 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.InterpretationGenes 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.FundingThis work was supported by a Seed Network grant from the Chan Zuckerberg Initiative to M.C.N. and by the European Union’s H2020 Research and Innovation Program under grant agreement no. 874656 (discovAIR) to M.C.N. U BIOPRED was supported by an Innovative Medicines Initiative Joint Undertaking (No. 115010), resources from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution (www.imi.europa.eu). Longfonds Junior Fellowship. We acknowledge the contribution of the whole U-BIOPRED team as listed in the Appendix S1.’ SDB, FM and RFS would like to thank the Helmholtz Association, Germany, for support.” NIH K08HL146943; Parker B. Francis Fellowship; ATS Foundation/Boehringer Ingelheim Pharmaceuticals Inc. Research Fellowship in IPF. RCR is part funded by Cancer Research UK Cambridge Centre and the Cambridge NIHR Biomedical Research Centre. BAP was funded by programme support from Cancer Research UK. The CRUKPAP Study was supported by the CRUK Cambridge Cancer Centre, by the NIHR Cambridge Biomedical Research Centre and by the Cambridge Bioresource. PIAMA was supported by The Netherlands Organization for Health Research and Development; The Netherlands Organization for Scientific Research; The Netherlands Lung Foundation (with methylation studies supported by AF 4.1.14.001); The Netherlands Ministry of Spatial Planning, Housing, and the Environment; and The Netherlands Ministry of Health, Welfare, and Sport. Dr. Qi is supported by a grant from the China Scholarship Council.