Instigators of COVID-19 in Immune Cells Are Increased in Tobacco Cigarette Smokers and Electronic Cigarette Vapers Compared With Nonsmokers

Abstract

Introduction The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus responsible for the COVID-19 pandemic, gains entry into the host cell when its Spike protein is cleaved by host proteases TMPRSS2 and furin, thereby markedly increasing viral affinity for its receptor, angiotensin-converting enzyme-2 (ACE2). In rodent and diseased human lungs, tobacco cigarette (TCIG) smoke increases ACE2, but the effect of electronic cigarette vaping (ECIG) is unknown. It is unknown whether nicotine (in both TCIGs and ECIGs) or non-nicotine constituents unique to TCIG smoke increase expression of key proteins in COVID-19 pathogenesis. Methods Immune (CD45+) cells collected before the pandemic in otherwise healthy young people, including TCIG smokers (n = 9), ECIG vapers (n = 12), or nonsmokers (NS) (n = 12), were studied. Using flow cytometry, expression of key proteins in COVID-19 pathogenesis were compared among these groups. Results TCIG smokers and ECIG vapers had similar smoking or vaping burdens as indicated by similar plasma cotinine levels. TCIG smokers compared with NS had a significantly increased percentage of cells that were positive for ACE2 (10-fold, p < .001), TMPRSS2 (5-fold, p < .001), and ADAM17 (2.5-fold, p < .001). Additionally, the mean fluorescence intensity (MFI) consistently showed greater mean ACE2 (2.2-fold, p < .001), TMPRSS2 (1.5-fold, p < .001), furin (1.1-fold, p < .05), and ADAM17 (2-fold, p < .001) in TCIG smokers compared with NS. In ECIG vapers, furin MFI was increased (1.15-fold, p < .05) and TMPRSS2 MFI tended to be increased (1.1-fold, p = .077) compared with NS. Conclusions The finding that key instigators of COVID-19 infection are lower in ECIG vapers compared with TCIG smokers is intriguing and warrants additional investigation to determine if switching to ECIGs is an effective harm reduction strategy. However, the trend toward increased proteases in ECIG vapers remains concerning. Implications (1) This is the first human study to report a marked increase in proteins critical for COVID-19 infection, including ACE2, TMPRSS2, and ADAM17, in immune cells from healthy tobacco cigarette smokers without lung disease compared with e-cigarette vapers and nonsmokers. (2) These findings warrant additional investigation to determine whether switching to electronic cigarettes may be an effective harm reduction strategy in smokers addicted to nicotine who are unable or unwilling to quit. (3) The increase in proteases in electronic cigarette vapers remains concerning.

Content Analysis of YouTube Videos Related to E-cigarettes and COVID-19

“…Propolis may be a healthy substance for strengthening immune systems (35); however, there is no evidence to support that use of these substances or vaping these substances can protect individuals from getting or treating COVID-19. Given that the effect of vaping such substances on COVID-19 is still unclear, (36)(37)(38)(39)(40) these videos are disseminating unconfirmed health information.…”

E-Cigarette Vapour Increases ACE2 and TMPRSS2 Expression in a Flavour- and Nicotine-Dependent Manner

“…Little work has been done in this area, but studies have shown that particulate matter (a known pathogenic component of cigarette smoke) increased ACE2 and TMPRSS2 expression in murine lung macrophages [ 66 ]. One study showed that ACE2 and TMPRSS2 was increased in CD45+ immune cells, which would include macrophages, of smokers and vapers [ 71 ]. Another study utilising a ferret SARS-CoV-2 infection model found that blood monocyte-derived macrophages were the most common infiltrated immune cells in the lungs, and the macrophages showed the presence of the virus.…”

Ectodomain shedding of proteins important for SARS-CoV-2 pathogenesis in plasma of tobacco cigarette smokers compared to electronic cigarette vapers: a cross-sectional study

“…All participants had refrained from smoking 12 h before the study session. Healthy male and female volunteers with previously described characteristics [11] between the ages of 21 years and 45 years were eligible for enrollment if they were chronic (> 1 year), as follows: (1) active TCIG smokers (regardless of the number of pack-years) or (2) ECIG vapers (no dual users) or (3) non-smokers. Former TCIG smokers were eligible to be included in the nonsmoker group, if greater than 1 year had elapsed since quitting.…”

“…End-tidal CO, elevated > 10 ppm in smokers, was measured in EC vapers and non-smokers to confirm none was surreptitiously smoking TCIGs. Current smoking/vaping burden was estimated by plasma cotinine levels as previously described [11]. The experimental protocols were approved by the UCLA Institutional Review Board (IRB#18-001,147), and all participants provided written informed consent.…”