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Principal Investigator: MATTHEW Lawrence SPRINGER
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2021
Award: $80,301
Funding agency: National Institute on Drug Abuse
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.”
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><Address><Affect><Binding Proteins><CATL><COVID-19><COVID-19 infection><COVID-19 predisposition><COVID-19 susceptibility><COVID-19 transmission><COVID-19 virus><COVID-19 virus transmission><COVID-19 vulnerability><COVID19><COVID19 infection><COVID19 virus><CTSL Protein><CV-19><CV19><Cannabis Smoking><Cardiovascular Models><Cathepsin B1><Cathepsin L><Cathepsins B><Cell Body><Cell surface><Cells><Cigarette><CoV-2><CoV2><Common Rat Strains><Communities><Coronavirus disease 2019 predisposition><Coronavirus disease 2019 susceptibility><Coronavirus disease 2019 vulnerability><Data><Drug usage><EC 3.4.22.1><Educational Mainstreaming><Electronic Nicotine Delivery Product><Electronic Nicotine Delivery Systems><Electronic cigarette><Epithelial><Epithelial Cells><Epitheliasin Gene><Esteroproteases><Exposure to><Gene Expression><Genes><Immunity><Individual><Infection><Inhalation Exposure><JUUL><JUUL aerosol><JUUL vapor><Knowledge><Learning><Ligand Binding Protein><Ligand Binding Protein Gene><Lung><Lung Alveolar Epithelia><Lung Respiratory System><Mainstreaming><Major Excreted Protein><Marijuana><Marijuana Smoking><Membrane><Molecular><Myocardium><NIDA><National Institute of Drug Abuse><National Institute on Drug Abuse><Nicotine><Opiates><Opioid><Outcome><PRSS10><Parents><Peptidases><Peptide Hydrolases><Population><Position><Positioning Attribute><Predisposed to COVID-19><Predisposed to SARS-CoV-2><Predisposed to Severe acute respiratory syndrome coronavirus 2><Predisposition><Protease Gene><Proteases><Protein Binding><Proteinases><Proteins><Proteolytic Enzymes><Rat><Rats Mammals><Rattus><Receptor Activation><Receptor Protein><Research><Risk><Risk Factors><SARS corona virus 2><SARS-CoV-2><SARS-CoV-2 infection><SARS-CoV-2 predisposition><SARS-CoV-2 susceptibility><SARS-CoV-2 transmission><SARS-CoV-2 vulnerability><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 predisposition><Severe acute respiratory syndrome coronavirus 2 susceptibility><Severe acute respiratory syndrome coronavirus 2 vulnerability><Severe acute respiratory syndrome related corona virus 2><Smoke><Smoking><Substance Use Disorder><Susceptibility><THC co-use><THC use><TMPRSS2><TMPRSS2 gene><Testing><Tetrahydrocannabinol co-use><Tetrahydrocannabinol use><Tobacco><Tobacco smoke><Tobacco smoking><Tobacco smoking behavior><Up-Regulation><Upregulation><Validation><Vascular Endothelium><Viral><Viral Diseases><Viral Receptor><Virus><Virus Diseases><Virus Receptors><Work><Wuhan coronavirus><achievement Mainstream Education><airway epithelium><alveolar epithelium><angiotensin converting enzyme 2><angiotensin converting enzyme II><base><bound protein><cannabis smoke><cannabis use><cannabis vaping><cardiac muscle><cigarette smoking><cigarette use><clinical decision-making><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 infection><coronavirus disease 2019 transmission><coronavirus disease 2019 virus><coronavirus disease 2019 virus transmission><drug use><e-cig><e-cig aerosols><e-cig vapor><e-cigarette><e-cigarette aerosols><e-cigarette vapor><e-vape><ecig><ecig aerosols><ecig vapor><ecigarette><ecigarette aerosols><ecigarette vapor><electronic cigarette aerosol><electronic cigarette vapor><electronic nicotine delivery device><electronic nicotine distribution system><electronic vape><experiment><experimental research><experimental study><hCoV19><heart muscle><heat-not-burn><heated tobacco products><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><interest><low nicotine cigarette><low nicotine content cigarette><marihuana><marijuana smoke><marijuana use><marijuana vaping><membrane structure><nCoV2><predisposed to Coronavirus disease 2019><prevent><preventing><public education><pulmonary><receptor><reduced nicotine cigarette><reduced nicotine content cigarette><response><severe acute respiratory syndrome coronavirus 2 transmission><substance use><substance using><susceptible to COVID-19><susceptible to Coronavirus disease 2019><susceptible to SARS-CoV-2><susceptible to Severe acute respiratory syndrome coronavirus 2><transmitted COVID-19><transmitted SARS-CoV-2><transmitted coronavirus disease 2019><transmitted severe acute respiratory syndrome coronavirus 2><vaping><viral infection><virus infection><virus-induced disease>