ACE-2 Expression in the Small Airway Epithelia of Smokers and COPD Patients: Implications for COVID-19

Leung, J. M.; Yang, C. X.; Tam, A.; Shaipanich, T.; Hackett, T. L.; Singhera, G. K.; Dorscheid, D. R.; Sin, D. D.

Introduction: Coronavirus disease 2019 (COVID-19) is a respiratory infection caused by the severe acute respiratory syndrome coronavirus2 (SARSCoV-2). This virus uses the angiotensin converting enzyme II (ACE2) as the cellular entry receptor to infect the lower respiratory tract. Because individuals with chronic obstructive pulmonary disease (COPD) are at increased risk of severe COVID19, we determined whether ACE2 expression in the lower airways was related to COPD and cigarette smoking. Methods: Using RNAseq, we determined gene expression levels in bronchial epithelia obtained from cytologic brushings of 6th to 8th generation airways in individuals with and without COPD. We externally validated these results from two additional independent cohorts, which used microarray technologies to measure gene expression levels from 6th to 12th generation airways. Results: In the discovery cohort (n=42 participants), we found that ACE2 expression levels were increased by 48% in the airways of COPD compared with non-COPD subjects (COPD=2.52 (0.66) log2 counts per million reads (CPM) versus non-COPD= 1.70 (0.51) CPM , p=.000762). There was a significant inverse relationship between ACE2 gene expression and FEV1% of predicted (r=negative 0.24; p=0.035). Current smoking also significantly increased ACE2 expression levels compared with never smokers (never current smokers=2.77 (90.91) CPM versus smokers=1.78 (0.39) CPM, p=0.024). These findings were replicated in the two external cohorts. Conclusions: ACE2 expression in lower airways is increased in patients with COPD and with current smoking. These data suggest that these two subgroups are at increased risk of serious COVID19 infection and highlight the importance of smoking cessation in reducing the risk.