Robert Tarran and colleagues in their recent study demonstrated that, cigarettes and e-cigarettes increase both ACE2 and SARS-CoV-2 spike protein binding and nicotine may be responsible for the increased spike protein binding and subsequent pseudovirus infection.
Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 spike protein directly binds with the host cell surface ACE2 receptor, a transmembrane metallocarboxypeptidase that is expressed in both membrane-anchored (mACE2) and soluble (sACE2) forms in the lung. Although mACE2 is responsible for viral entry, recent observations also suggest role of sACE2 in infection and severe COVID-19. It has been also suggested in recent studies that, the use of cigarettes and e-cigarettes reduces lung capacity and increases the risk of many respiratory infections and can increase the severity of respiratory diseases.
Thus, Robert Tarran and colleagues now tested the hypothesis that cigarettes and e-cigarettes could affect ACE2 activity and subsequent SARS-CoV-2 infection.
They first evaluated sACE2 activity in concentrated bronchoalveolar lavage fluid (BALF) samples from non-smokers, smokers and vapers and observed that sACE2 activity was significantly higher in bronchoalveolar lavage fluid from both smokers and vapers compared to age-matched non-smokers.
“Our current study provides further in vivo evidence that sACE2 is upregulated in smokers and vapers BALF”
They also grew human bronchial epithelial cultures (HBECs) at air-liquid interface in order to evaluate the impact of tobocco smoke on ACE2 activity. They found that, exposure to cigarette smoke increased ACE2 levels, mACE2 activity, and sACE2 in primary bronchial epithelial cultures. In addition, it also increases SARS-CoV-2 binding.
In addition, they explored the impact of cigarette smoke condensate (CSC) and e-liquid exposure on pseudovirus infection in primary tracheobronchial and small airway epithelia. It has been found that, treatment with either cigarette smoke condensate or e-liquid increased infections with a spike-coated SARS-CoV2 pseudovirus.
Finally, they suggested that, the increase in sACE2 most likely reflects an overall increase in cellular ACE2 expression. In addition, they hypothesized that, nicotine may be responsible for the increased spike protein binding and subsequent pseudovirus infection. However, the underlying mechanisms, and the purported link to nicotine will require additional study.
“Overall, our observations indicated that tobacco product use elevates ACE2 activity and increases the potential for SARS-CoV-2 infection through enhanced spike protein binding. Importantly, our results strongly urge consideration of vaping as a risk factor for COVID-19.”— concluded authors of the study
Featured image: Tobacco smoking increases ACE2 activity and SARS-CoV-2 infection. Bronchoalveolar lavage fluids from non-smokers, smokers, and vapers (n=10 each) were concentrated and ACE2 activity was measured using 50 µM specific fluorogenic substrates. Cleaved substrate derived fluorescence as arbitrary unit (AU) following one hour of reaction was reported (A). Human bronchial epithelial cells (HBECs) were cultures at air-liquid interface (ALI) and exposed to smoke from one cigarette per day for one (acute) or four days (chronic). Apical surface was washed with PBS to collect the mucosal secretion and 50 µM fluorogenic substrate was added on the apical surface to evaluate apical ACE2 activity. ACE2 activity on apical side of acute and chronic smoke exposed cultures and corresponding apical washes (B) were reported. Activities are presented as accumulated fluorescence in arbitrary units (AU) of the cleaved products following 10 minutes of reaction. Whole cell lysates were collected from chronically cigarette smoke exposed cultures, and ACE2 and GAPDH protein expressions were evaluated by immunoblotting. Representative blots were shown and GAPDH normalized ACE2 expression in air and smoke exposed cultures as fold change (C) was reported. (D) Acute or chronically smoke exposed cultures were apically exposed to spike pseudovirus suspension and the resulting DsRed marker fluorescence was recorded after three days. Data represented as median, lower and upper quartiles; n=8-9 per group; p-values were provided on the graph. © Robert Tarran et al.
Reference: Arunava Ghosh, Vishruth Girish, Monet Lou Yuan, Raymond D. Coakley, Neil E. Alexis, Erin L Sausville, Anand Vasudevan, Alexander R. Chait, Jason Meyer Sheltzer, Robert Tarran, “Combustible and electronic cigarette exposures increase ACE2 activity and SARS-CoV-2 Spike binding”, bioRxiv 2021.06.04.447156; doi: https://doi.org/10.1101/2021.06.04.447156
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