Combustible and Electronic Cigarette Exposures Increase ACE2 Activity and SARS-CoV-2 Spike Binding

Ghosh, Arunava; Girish, Vishruth; Yuan, Monet Lou; Coakley, Raymond D.; Wrennall, Joe A; Alexis, Neil E.; Sausville, Erin L.; Vasudevan, Anand; Chait, Alexander R.; Sheltzer, Jason M.; Tarran, Robert

doi:10.1164/rccm.202106-1377le

Cited by 10 publications

(16 citation statements)

References 19 publications

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“…Most prior SARS-CoV-2 studies have focused on ACE2 expression [20, 30, 31, 33, 34], and did not examine the effects of EC chemicals on TMPRSS2 concentration and activity. Increased TMPRSS2 activity would promote spike cleavage at the S2’ site, internally to the S2 subunit, and fully activate the viral fusion process [12, 66].…”

Section: Discussionmentioning

confidence: 99%

“…TMPRRS2 expression was differentially regulated in different respiratory cell types of smokers [18]. Studies that directly examined viral entry into human cells concluded that cigarette smoking increases SARS-CoV-2 infection [19, 20]. One group further showed that cigarette smoking inhibited the airway basal cell repair processes and reduced the response of the innate immune system by suppressing interferon β-1 [19], both factors that may contribute to the severity of the disease.…”

Section: Introductionmentioning

confidence: 99%

“…Several in vivo studies with mice and in vitro studies with human cells have investigated the effects of vaping and SARS-CoV-2 infection. Elevated ACE2 activities were found in the bronchial-lavage fluid from EC users and smokers [20]. Full body exposures to “Mint” but not “Mango” aerosols generated from JUUL™ pods increased ACE2 levels in mouse lung [30].…”

Section: Introductionmentioning

confidence: 99%

“…BEAS-2B cells treated with e-liquids in submerged culture showed that PG/VG elevated ACE2 mRNA expression, and the effect was dependent on other chemicals in the e-liquid mixture [34]. JUUL™ “Virginia Tobacco” e-liquid increased infection in primary tracheobronchial and small airway epithelium in submerged culture [20]; however, e-liquid rather than authentic aerosol was tested.…”

Section: Introductionmentioning

confidence: 99%

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New Insights into How JUUL™ Electronic Cigarette Aerosols and Aerosol Constituents Affect SARS-CoV-2 Infection of Human Bronchial Epithelial Cells

Phandthong

Wong

Song

et al. 2022

Preprint

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Background: The relationship between the use of tobacco products and SARS-CoV-2 infection is poorly understood and controversial. Most studies have been done with tobacco cigarettes, while few have examined the effect of electronic cigarettes (ECs) on SARS-CoV-2 infection. We tested the hypothesis that EC fluids and aerosols with high concentrations of nicotine promote SARS-COV-2 infection by increasing viral entry into human respiratory epithelial cells. Methods: Responses of BEAS-2B cells to authentic JUUL aerosols or their individual constituents (propylene glycol (PG)/vegetable glycerin (VG) and nicotine) were compared using three exposure platforms: submerged culture, air-liquid-interface (ALI) exposure in a cloud chamber, and ALI exposure in a Cultex system, which produces authentic heated EC aerosols. SARS-CoV-2 infection machinery was assessed using immunohistochemistry and Western blotting. Specifically, the levels of the SARS-CoV-2 receptor ACE2 (angiotensin converting enzyme 2) and a spike modifying enzyme, TMPRSS2 (transmembrane serine protease 2), were evaluated. Following each exposure, lentivirus pseudoparticles with spike protein and a green-fluorescent reporter were used to test viral penetration and the susceptibility of BEAS-2B cells to infection. Results: Nicotine, EC fluids, and authentic JUUL aerosols increased both ACE2 levels and TMPRSS2 activity, which in turn increased viral particle entry into cells. While most data were in good agreement across the three exposure platforms, cells were more responsive to treatments when exposed at the ALI in the Cultex system, even though the exposures were brief and intermittent. In the Cultex system, PG/VG, PG/VG/nicotine, and JUUL aerosols significantly increased infection above clean air controls. However, both the PG/VG and JUUL treatments were significantly lower than nicotine/PG/VG. PG/VG increased infection only in the Cultex system, which produces heated aerosol. Conclusion: Our data are consistent with the conclusion that authentic JUUL aerosols or their individual constituents (nicotine or PG/VG) increase SARS-CoV-2 infection. The strong effect produced by nicotine was modulated in authentic JUUL aerosols, demonstrating the importance of studying mixtures and aerosols from actual EC products. These data support the idea that vaping increases the likelihood of contracting COVID-19.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

New Insights into How JUUL™ Electronic Cigarette Aerosols and Aerosol Constituents Affect SARS-CoV-2 Infection of Human Bronchial Epithelial Cells

Phandthong

Wong

Song

et al. 2022

Preprint

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“…In the weeks following the pre-print publication of these data, social media platforms like Twitter relayed thousands of messages about the benefits of smoking or vaping in the context of COVID-19 [ 31 , 32 ]. However, the effects of nicotine and cigarette smoke on SARS-CoV-2 replication and the expression of its entry receptor ACE2 remain highly controversial with recent reports of both increased [ 33 , 34 ] and decreased [ 35 ] ACE2 levels. Alternatively, cumulative smoking exposure (in former or current smokers) was constantly associated with worse outcomes for COVID-19 [ 11 , 36 – 38 ].…”

Section: Discussionmentioning

confidence: 99%

Nicotine patches in patients on mechanical ventilation for severe COVID-19: a randomized, double-blind, placebo-controlled, multicentre trial

Labro

Tubach²,

Belin³

et al. 2022

Intensive Care Med

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Purpose Epidemiologic studies have documented lower rates of active smokers compared to former or non-smokers in symptomatic patients affected by coronavirus disease 2019 (COVID-19). We assessed the efficacy and safety of nicotine administered by a transdermal patch in critically ill patients with COVID-19 pneumonia. Methods In this multicentre, double-blind, placebo-controlled trial conducted in 18 intensive care units in France, we randomly assigned adult patients (non-smokers, non-vapers or who had quit smoking/vaping for at least 12 months) with proven COVID-19 pneumonia receiving invasive mechanical ventilation for up to 72 h to receive transdermal patches containing either nicotine at a daily dose of 14 mg or placebo until 48 h following successful weaning from mechanical ventilation or for a maximum of 30 days, followed by 3-week dose tapering by 3.5 mg per week. Randomization was stratified by centre, non- or former smoker status and Sequential Organ Function Assessment score (< or ≥ 7). The primary outcome was day-28 mortality. Main prespecified secondary outcomes included 60-day mortality, time to successful extubation, days alive and free from mechanical ventilation, renal replacement therapy, vasopressor support or organ failure at day 28. Results Between November 6th 2020, and April 2nd 2021, 220 patients were randomized from 18 active recruiting centers. After excluding 2 patients who withdrew consent, 218 patients (152 [70%] men) were included in the analysis: 106 patients to the nicotine group and 112 to the placebo group. Day-28 mortality did not differ between the two groups (30 [28%] of 106 patients in the nicotine group vs 31 [28%] of 112 patients in the placebo group; odds ratio 1.03 [95% confidence interval, CI 0.57–1.87]; p = 0.46). The median number of day-28 ventilator-free days was 0 (IQR 0–14) in the nicotine group and 0 (0–13) in the placebo group (with a difference estimate between the medians of 0 [95% CI -3–7]). Adverse events likely related to nicotine were rare (3%) and similar between the two groups. Conclusion In patients having developed severe COVID-19 pneumonia requiring invasive mechanical ventilation, transdermal nicotine did not significantly reduce day-28 mortality. There is no indication to use nicotine in this situation. Supplementary Information The online version contains supplementary material available at 10.1007/s00134-022-06721-1.

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Recognizing risk factors associated with poor outcomes among patients with COVID-19

Rodriguez‐Miguelez

Heefner

Carbone

2023

Progress in Cardiovascular Diseases

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Combustible and Electronic Cigarette Exposures Increase ACE2 Activity and SARS-CoV-2 Spike Binding

Cited by 10 publications

References 19 publications

New Insights into How JUUL™ Electronic Cigarette Aerosols and Aerosol Constituents Affect SARS-CoV-2 Infection of Human Bronchial Epithelial Cells

New Insights into How JUUL™ Electronic Cigarette Aerosols and Aerosol Constituents Affect SARS-CoV-2 Infection of Human Bronchial Epithelial Cells

Nicotine patches in patients on mechanical ventilation for severe COVID-19: a randomized, double-blind, placebo-controlled, multicentre trial

Recognizing risk factors associated with poor outcomes among patients with COVID-19

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