Upregulation of SARS-CoV-2 receptor and activation proteases by marijuana smoke and e-cigarette aerosols

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PROJECT SUMMARY This urgent competitive revision will support a rapid response effort to determine if cigarette smoking-induced changes in airway epithelium that make it more susceptible to SARS-CoV-2 infection also result from marijuana smoking (smoke without nicotine), or from use of electronic nicotine delivery systems (ENDS) including e-cigarettes and the heated tobacco product IQOS (i.e., nicotine without smoke), including secondhand exposure. Tobacco smoke is thought to increase susceptibility to COVID-19 by increasing expression of the SARS-CoV-2 receptor, ACE2, on specific subsets of alveolar epithelial cells. This knowledge has led to advice to the public that smoking may increase the risk of COVID-19 transmission and progression. There are not specific data about smoking cannabis or vaping, so clinical decision making and public education is limited to a general admonition that vaping and smoking are harmful to pulmonary immunity. The parent R21 involves exposing rats to smoke from marijuana. The research team also has the capability to expose rats to aerosol from e-cigarettes including JUUL, aerosol from IQOS, and smoke from Marlboro Red cigarettes. This urgent competitive revision will permit additional experiments to determine (1) if use of marijuana, JUUL, or IQOS can cause the same increase in ACE2 gene expression as does smoking tobacco; (2) if this upregulation is a result of nicotine or smoke or both; (3) if these exposures similarly upregulate expression of the virus’ main activation protease TMPRSS2 or the alternative activation proteases cathepsin B or L; (4) if upregulation occurs in ocular epithelium, vascular endothelium, and myocardium; (5) if the upregulation of these genes is also caused by secondhand exposure; and (6) if cessation might then reduce expression. These findings will help to prevent or mitigate community spread of COVID-19, especially in substance-using populations. Specific Aim 1 is to determine if main- stream exposure to smoke from marijuana, aerosol from JUUL e-cigarettes or IQOS, or smoke from Marlboro or reduced-nicotine cigarettes, affects expression of ACE2, TMPRSS2, cathepsin B, or cathepsin L. Specific Aim 2 is to determine if secondhand exposure to the products studied in Aim 1 also affects expression of ACE2, TMPRSS2, cathepsin B, or cathepsin L. This proposal is directly responsive to the stated purpose and research objectives of the NOSI: “NIDA is especially interested in research collecting and examining data on the risks and outcomes for COVID-19 infection in individuals suffering from substance use disorders… determine whether substance use (especially smoking tobacco or marijuana, vaping, opioids and other drug use) is a risk factor for the onset and progression of COVID-19.”