Airways Expression of SARS-CoV-2 Receptor, ACE2, and TMPRSS2 Is Lower in Children Than Adults and Increases with Smoking and COPD

Abstract

It has been reported that angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are the main cell entry proteins for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and play a critical role in causing coronavirus disease 2019 (COVID-19). To investigate the expression level of these SARS-CoV-2 host cell entry genes in the lung airway, we used public gene expression datasets. We have found a differential expression of ACE2 and TMPRSS2 in nasal and bronchial airways relative to age and diseases status. Children were found to have significantly lower expression of COVID-19 receptors in the upper and lower airways (nasal and bronchial). Moreover, the lung airway expression of both ACE2 and TMPRSS2 was found to be significantly upregulated in smokers compared with non-smokers, and in patients with chronic obstructive pulmonary disease (COPD) compared with healthy subjects. No difference was observed in the blood expression levels of ACE2 and TMPRSS2 between children and adults, or in COPD or diabetic patients. However, a significant increase in blood expression levels of these genes was observed in patients with essential hypertension, whereas only ACE2 was upregulated in the blood of asthmatics. These results suggest that the observed difference in COVID-19 severity between children and adults could, in part, be attributed to the difference in ACE2 and TMPRSS2 airways tissue expression levels.

Keywords: ACE2; COPD; COVID-19; Children; SARS-CoV-2; TMPRSS2; bronchial; hypertension; nasal epithelium; smoking.

Graphical abstract

Figure 1

Microarray Expression Levels of ACE2 and TMPRSS2 in PBMCs, Upper and Lower Respiratory Tract of Children and Adults (A) There was no difference in expression levels of ACE2 and TMPRSS2 in PBMCs of adults versus children. (B) Nasal and bronchial expression levels of ACE2 and TMPRSS2 were significantly lower in children versus adults. (C) Expression levels of ACE2 and TMPRSS2 were significantly higher in nasal versus bronchial tissue of children. (D) In adults, the expression levels of ACE2 and TMPRSS2 decreased moving from upper to lower airways. The nasal expression of these genes was significantly higher in nasal versus bronchial and in nasal versus small airways. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, ∗∗∗∗p < 0.0001. Results are presented as mean (± SEM) mRNA expression.

Figure 2

ACE2 and TMPRSS2 Are Significantly Higher in Lungs of COPD Patients and PBMCs of Hypertension Patients (A) Compared with healthy controls, the levels of ACE2 and TMPRSS2 were higher in lungs of COPD patients, as well as in lungs of smokers. (B) No difference was found in expression levels of asthmatics bronchial tissue versus healthy controls. (C) Also, there were no differences in levels of these genes in lung tissue of idiopathic pulmonary fibrosis versus healthy controls. (D) The levels of ACE2 and TMPRSS2 expression were found to be significantly elevated in PBMCs of hypertensive versus healthy controls. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, ∗∗∗∗p < 0.0001. Results are presented as mean (± SEM) mRNA expression.

Figure 3

Effect of SARS-CoV Infection in Expression Levels of ACE2 and TMPRSS2 in Lung Epithelial Cells (Calu-3) (A) ACE2 expression was significantly decreased at 24- and 48-h time points following infections. (B) However, no significant change in the expression of TMPRSS2 was observed following infection with SARS-CoV-1. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, ∗∗∗∗p < 0.0001. Results are presented as mean (± SEM) mRNA expression.