We recently reported that current smokers and those with COPD had higher airway epithelial cell expression of the angiotensin-converting enzyme II (ACE-2) viral entry receptor [1]. We thus read with great interest the work of P. Russo and co-workers, 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.
Short abstract
α7-nAChR may upregulate ACE-2 https://bit.ly/2xS0cfT
From the authors:
We recently reported that current smokers and those with COPD had higher airway epithelial cell expression of the angiotensin-converting enzyme II (ACE-2) viral entry receptor [1]. We thus read with great interest the work of P. Russo and co-workers, 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 (Pearson r=0.54, p=2.31×10−8) (figure 1). There was significantly higher CHRNA7 expression in those with COPD (2.75±0.73 versus 2.14±0.43 in those without COPD; p=1.47×10−4), 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=6.16×10−2). CHRNA7 was also negatively correlated with forced expiratory volume in 1 s percent predicted (Pearson r=−0.37, p=2.83×10−4). Interestingly, CHRNA7 was positively if weakly correlated with body mass index (Pearson r=0.14, p=6.31×10−3), 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 coronavirus disease 2019 (COVID-19) cases [2].
FIGURE 1.
Transcriptome profiles generated through RNA-Seq of airway epithelial cells demonstrated a significant positive correlation between ACE2 and CHRNA7 expression.
Together, these data further help to characterise the connections between airway epithelial ACE-2, and 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 [3], Alzheimer's disease [4] and Parkinson's disease [5] 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 [6] and the idea of potentially repurposing these compounds for a pandemic with few therapeutic options currently available is certainly appealing. Whether α7-nAChR-selective antagonists, such as methyllycaconitine [7] and α-conotoxin [8], can meaningfully alter ACE-2 expression to prevent severe acute respiratory syndrome coronavirus 2 entry into the airway epithelium seems the next logical investigation in our furious pursuit for better therapeutics.
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Conflict of interest: J.M. Leung has nothing to disclose.
Conflict of interest: C.X. Yang has nothing to disclose.
Conflict of interest: D.D. Sin reports grants from Merck, personal fees for advisory board work from Sanofi-Aventis and Regeneron, grants and personal fees for lectures from Boehringer Ingelheim and AstraZeneca, personal fees for lectures and advisory board worm from Novartis, outside the submitted work.
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