Smoking and COVID-19: Similar bronchial ACE2 and TMPRSS2 expression and higher TMPRSS4 expression in current versus never smokers

Uncertainties remain concerning the pathophysiology, epidemiology, and potential therapeutics for COVID-19. Among unsettled controversies is whether tobacco smoking increases or protects from severe COVID-19. Several epidemiological studies reported reduced COVID-19 hospitalizations among smokers, while other studies reported the opposite trend. Some authors assumed that smokers have elevated airway expression of ACE2, the cell recognition site of the SARS-Cov-2 spike protein, but this suggestion remains unverified. We therefore performed data mining of two independent NCBI GEO genome-wide RNA expression files (GSE7894 and GSE994) and report that in both data sets, current smokers and never smokers have, on average, closely similar bronchial epithelial cell mRNA levels of ACE2, as well as TMPRSS2, coding for a serine protease priming SARS-Cov-2 for cell entry, and ADAM17, coding for a protease implicated in ACE2 membrane shedding. In contrast, the expression levels of TMPRSS4, coding for a protease that primes SARS-CoV-2 for cell entry similarly to TMPRSS2, were elevated in bronchial epithelial cells from current smokers compared with never smokers, suggesting that higher bronchial TMPRSS4 levels in smokers might put them at higher SARS-Cov-2 infection risk. The effects of smoking on COVID-19 severity need clarification with larger studies. Additionally, the postulated protective effects of nicotine and nitric oxide, which may presumably reduce the risk of a “cytokine storm” in infected individuals, deserve assessment by controlled clinical trials.