key: cord-0912898-x2htgrrt
authors: Leung, Janice M.; Yang, Chen Xi; Sin, Don D.
title: COVID-19 and Nicotine as a Mediator of ACE-2
date: 2020-04-29
journal: Eur Respir J
DOI: 10.1183/13993003.01261-2020
sha: 2c98c1722d475d45c5eac30a1925d929c42c87d6
doc_id: 912898
cord_uid: x2htgrrt

α7-nAChR may upregulate ACE-2

We recently reported that current smokers and those with COPD had higher airway epithelial cell expression of the angiotensin-converting enzyme-2 (ACE-2) viral entry receptor [1] . We thus read with great interest the work of Russo et al. [2] which proposes a mechanism for this finding, namely that this upregulation is mediated by nicotine exposure specifically through the α7 subtype of nicotine acetylcholine receptors (α7-nAChR). While exposure to increasing concentrations of nicotine caused epithelial cells to increase ACE-2 levels, subsequent gene silencing of α7-nAChR appeared to significantly dampen this response. A secondary transcriptome sequencing analysis of our cohort (consisting of 42 subjects who underwent bronchoscopy for epithelial cell brushings [1] ) reveals evidence in support of this hypothesis. We found that airway epithelial cell expression of CHRNA7, encoding α7-nAChR, was significantly correlated with the expression of ACE2 (Figure 1 , Pearson r=0.54, p=2.31x10 -8 ). There was significantly higher CHRNA7 expression in those with COPD (2.75±0.73 vs. 2.14±0.43 in those without COPD, p=1.47x10 -4 ), with a trend towards higher expression in current smokers compared to former and never smokers (2.86±0.92 in current smokers, 2.35±0.57 in former smokers, and 2.27±0.45 in never smokers, p=6.16x10 -2 ). CHRNA7 was also negatively correlated with forced expiratory volume in 1 second percent predicted (Pearson r=-0.37, p=2.83x10 -4 ). Interestingly, CHRNA7 was positively if weakly correlated with body mass index (Pearson r=0.14, p=6.31x10 -3 ), raising the intriguing possibility that nicotine receptor mediation of ACE-2 may also be related to why obese individuals have made up a considerable proportion of COVID-19 cases [3] .

Together, these data further help to characterize the connections between airway epithelial ACE-2, α7-nAChR, and the unique vulnerability of patients with COPD to severe COVID-19. α7-nAChR's widespread abundance in the human body, from neuronal tissue to immune cells to the lung and digestive tract, and its various roles in diseases such as schizophrenia [4] , Alzheimer's disease [5] , and Parkinson's disease [6] has meant that considerable work has already been done to target α7-nAChR as a therapeutic modality. As an example, α7-nAChR antagonists for the purpose of smoking cessation have long been proposed [7] and the idea of potentially repurposing these compounds for a pandemic with few therapeutic options currently available is certainly appealing. Whether α7-nAChRselective antagonists such as methyllycaconitine [8] and α-conotoxin [9] can meaningfully alter ACE-2 expression to prevent SARS-CoV-2 entry into the airway epithelium seems the next logical investigation in our furious pursuit for better therapeutics. 

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