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