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

Abstract

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. One week after initial symptoms develop, a subset of patients progresses to severe disease, with high mortality and limited treatment options. To design novel interventions aimed at preventing spread of the virus and reducing progression to severe disease, detailed knowledge of the cell types and regulating factors driving cellular entry is urgently needed. Here we assess the expression patterns in genes required for COVID-19 entry into cells and replication, and their regulation by genetic, epigenetic and environmental factors, throughout the respiratory tract using samples collected from the upper (nasal) and lower airways (bronchi). Matched samples from the upper and lower airways show a clear increased expression of these genes in the nose compared to the bronchi and parenchyma. Cellular deconvolution indicates a clear association of these genes with the proportion of secretory epithelial cells. Smoking status was found to increase the majority of COVID-19 related genes including ACE2 and TMPRSS2 but only in the lower airways, which was associated with a significant increase in the predicted proportion of goblet cells in bronchial samples of current smokers. Both acute and second hand smoke were found to increase ACE2 expression in the bronchus. Inhaled corticosteroids decrease ACE2 expression in the lower airways. No significant effect of genetics on ACE2 expression was observed, but a strong association of DNA- methylation with ACE2 and TMPRSS2- mRNA expression was identified in the bronchus.

Chronic lung diseases are associated with gene expression programs favoring SARS-CoV-2 entry and severity

“…TMPRSS2 expression is highest in AT2 cells, and is lower in the COPD samples ( Supplementary Fig. 4b), similar to a recent publication demonstrating decreased TMPRSS2 expression in severe COPD 42 . Two alternative priming proteases (CTSL and FURIN) showed no significant differences in expression between control and disease samples ( Supplementary Fig.…”

“…Leung et al performed bulk RNAseq and immunohistochemical staining on bronchial epithelial cells and showed significantly elevated expression levels of ACE2 and ACE2 protein in the small airways of COPD patients compared to control 70 . Another study on bronchoscopically isolated tissue showed no relationship between disease status (mild to moderate asthma or COPD) on the expression levels of all SARS-CoV-2 entry factors 42 . Our study utilized scRNAseq technology to study gene expression at a very granular level and did not identify increased ACE2 expression at the single cell level in CLD, including COPD.…”

Chronic lung diseases are associated with gene expression programs favoring SARS-CoV-2 entry and severity

“…TMPRSS2 expression is highest in AT2 cells, and is lower in the COPD samples ( Supplementary Fig. 4b), similar to a recent publication demonstrating decreased TMPRSS2 expression in severe COPD 42 . Two alternative priming proteases (CTSL and FURIN) showed no signi cant differences in expression between control and disease samples ( Supplementary Fig.…”

“…Leung et al performed bulk RNAseq and immunohistochemical staining on bronchial epithelial cells and showed signi cantly elevated expression levels of ACE2 and ACE2 protein in the small airways of COPD patients compared to control 70 . Another study on bronchoscopically isolated tissue showed no relationship between disease status (mild to moderate asthma or COPD) on the expression levels of all SARS-CoV-2 entry factors 42 . Our study utilized scRNAseq technology to study gene expression at a very granular level and did not identify increased ACE2 expression at the single cell level in CLD, including COPD.…”

Tobacco use as a well-recognized cause of severe COVID-19 manifestations

“…proliferation in epithelial cells through co-expression of ACE2 [24]. Smoking status was found to increase the majority of COVID-19 related genes in the lower airways, which was associated with a significant increase in the predicted proportion of goblet cells in bronchial samples of smokers [25]. Smoking-mediated upregulation of the androgen pathway also leads to an increased SARS-CoV-2 susceptibility [26].…”