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Principal Investigator: URSZULA T IWANIEC
Organization: OREGON STATE UNIVERSITY
Fiscal Year: 2021
Award: $72,235
Funding agency: National Institute on Alcohol Abuse and Alcoholism
PROJECT SUMMARY
SARS-CoV-2, the viral cause of Coronavirus Disease 2019 (COVID-19), is a highly contagious coronavirus,
which upon infection results in a non-uniform distribution of clinical response. SARS-CoV-2 infects the lung and
other organs, including liver and immune system, with non-lung infections contributing to the etiology of severe
COVID-19. Co-morbidity factors associated with poorer health outcomes include male sex, older age, and
disease. However, these do not fully explain the distribution of COVID-19 severity, suggesting additional
modifying factors. Based on the molecular mechanisms mediating viral infection, excessive alcohol
consumption may be an unrecognized factor influencing SARS-CoV-2 infection. Spike proteins on the surface
of SARS-CoV-2, and host serine proteases (such as furin and TMPRSS2) and ACE2-expressing receptor sites
on target cells are required for SARS-CoV-2 infection. Conversely, ADAM17 (TACE), a major sheddase of
ACE2, may lower infection. There is strong circumstantial evidence that alcohol directly increases risk for
COVID-19 by altering levels of the enzymes and membrane proteins essential for SARS-CoV-2 infection.
Growth hormone/ insulin-like growth factor-1 (GH/IGF-1) and androgen signaling are disturbed by alcohol.
GH/IGF-1 signaling is important for regulating levels of furin and ACE2. Androgen signaling is the only known
regulator of TMPRSS2 gene transcription, suggesting a plausible mechanism for male sex as a risk factor for
severe COVID-19. Additionally, alcohol lowers ADAM17 levels and increases levels of the adipocyte-derived
hormone leptin; Adam17 and leptin are important modulators of immune response to viral infection. Based on
the literature and preliminary data, we hypothesize alcohol consumption results in undesirable levels of plasma
and target cell membrane proteins necessary for or opposing SARS-CoV-2 infection. To test this hypothesis,
we propose one Specific Aim: Evaluate the effects of alcohol – in the context of sex, age, and weight – on
protein and/or gene expression levels of molecular factors influencing SARS-CoV-2 infection (e.g., ACE2, furin,
TMPRSS2 and ADAM17) in archived tissues (plasma, lung, liver, abdominal fat, and bone marrow) from male
and female rhesus macaques. The macaques were subjected to voluntary alcohol intake that mimics the full
range of human drinking behavior (www.MATRR.com). The proposed research will provide insight into alcohol
consumption as a potential life-style factor for increasing risk for infection by SARS-CoV-2 and contributing to
poorer health outcomes following infection. The research will also help identify potential interactions between
alcohol consumption and intrinsic factors such as sex, age and weight in influencing COVID-19 outcome. The
requested supplement is a logical extension of the parent proposal (R01AA026289: Complex Systems
Analysis of the Impact of Alcohol on Bone in Non-Human Primates) designed to: (1) determine the contribution
of invariant intrinsic factors (e.g., age, sex, species) and variable extrinsic factors (e.g., drinking pattern) on
organ effects of alcohol (original focus on bone), and (2) identify the contribution of hormones/cytokines.
Terms: <21+ years old><Absolute ethanol><Adult><Adult Human><Affect><Age><Age of Onset><Alcohol Chemical Class><Alcohol Drinking><Alcohol abuse><Alcohol consumption><Alcoholic Beverages><Alcohols><Animal Model><Animal Models and Related Studies><Animals><Biochemical Markers><Blood><Blood Reticuloendothelial System><Blood Serum><Body Tissues><Bone Density><Bone Mineral Density><Caloric Intake><Cell Body><Cell Count><Cell Number><Cells><Chronic><Common Rat Strains><Complex><Crab-Eating Macaque><Crab-Eating Monkey><Cynomolgus Monkey><Cynomolgus macaque><Data><Diet><ETOH><ETOH level><Economics><Endocrine Gland Secretion><Energy Intake><EtOH abuse><EtOH drinking><EtOH use><Ethanol><Ethyl Alcohol><Failure><Female><Fracture><Goals><Grain Alcohol><Grant><Health><Hormones><Human><Individual><Intake><Intervention Studies><Intrinsic factor><Lead><Light><Linear Regressions><M fascicularis><M mulatta><M. fascicularis><M. mulatta><Macaca><Macaca fascicularis><Macaca mulatta><Macaque><Machine Learning><Mediating><Metabolic dysfunction><Methylcarbinol><Modeling><Modern Man><Molecular><Monkeys><NIAAA><National Institute on Alcohol Abuse and Alcoholism><Oregon><Organ><Organ System><Outcome><Pathology><Pattern><Pb element><Peptide Hormone Gene><Photoradiation><Physiologic><Physiological><Population><Primates><Primates Mammals><Proteins><R-Series Research Projects><R01 Mechanism><R01 Program><Rat><Rats Mammals><Rattus><Research><Research Grants><Research Project Grants><Research Projects><Research Specimen><Rhesus><Rhesus Macaque><Rhesus Monkey><Risk Factors><Serum><Site><Skeleton><Specimen><Strategic Planning><System><Systems Analyses><Systems Analysis><Testing><Therapeutic Hormone><Therapeutic Steroid Hormone><Tissues><Transcend><United States><Variant><Variation><adulthood><ages><alcohol co-abuse><alcohol effect><alcohol ingestion><alcohol intake><alcohol level><alcohol measurement><alcohol problem><alcohol product use><alcohol related research><alcohol research><alcohol response><alcohol use><alcoholic beverage consumption><alcoholic drink intake><base><body system><bone><bone cell><bone fracture><bone health><bone mass><bone metabolism><bone turnover><caloric dietary content><cytokine><density><diets><drinking><drinking behavior><drinking onset><ethanol abuse><ethanol consumption><ethanol drinking><ethanol effect><ethanol ingestion><ethanol intake><ethanol measurement><ethanol product use><ethanol research><ethanol response><ethanol use><ethyl alcohol measurements><fracture risk><hazardous alcohol use><heavy metal Pb><heavy metal lead><insight><intervention research><interventional research><interventional study><interventions research><machine learned><male><model of animal><model organism><multidisciplinary><non-human primate><nonhuman primate><nutrient metabolism><peptide hormone><problem alcohol use><problem drinking><problematic alcohol consumption><problematic alcohol use><response to alcohol><response to ethanol><sex><skeletal><small molecule><social><steroid hormone>