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Principal Investigator: URSZULA T IWANIEC
Organization: OREGON STATE UNIVERSITY
Fiscal Year: 2020
Award: $73,720
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: <2019 novel coronavirus><2019-nCoV><Adipocytes><Adipose Cell><Administrative Supplement><Adult-Onset Diabetes Mellitus><Age><Alcohol Chemical Class><Alcohol Drinking><Alcohol consumption><Alcohols><Androgenic Agents><Androgenic Compounds><Androgens><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Archives><Blood Plasma><Body Tissues><Bone Marrow><Bone Marrow Reticuloendothelial System><CD143 Antigens><COVID-19><COVID19><Carboxycathepsin><Cardiovascular Diseases><Causality><Cell Body><Cell Communication and Signaling><Cell Membrane Proteins><Cell Signaling><Cells><Clinical Distribution><Complex><Coronaviridae><Coronavirus><Data><Dietary Alcohol><Dipeptidyl Peptidase A><Disease><Disorder><Drug Targeting><Endocrine Gland Secretion><Enzyme Gene><Enzymes><Epitheliasin Gene><Esteroproteases><EtOH drinking><EtOH use><Etiology><Fat Cells><Female><Funding><Gene Expression><Gene Transcription><Genetic Transcription><Grant><Growth Hormone><Growth Hormone 1><Health><Heavy Drinking><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Hormones><Human><Hypertension><IGF-1><IGF-I><IGF-I-SmC><IMiD><Immune modulatory therapeutic><Immune response><Immune system><Immunological response><Immunomodulators><Individual><Infection><Insulin-Like Growth Factor 1><Insulin-Like Growth Factor I><Insulin-Like Somatomedin Peptide I><Intracellular Communication and Signaling><Intrinsic factor><Ketosis-Resistant Diabetes Mellitus><Kininase A><Kininase II><Knowledge><Leptin><Libraries><Life><Lipocytes><Literature><Liver><Liver Cells><Lung><Lung Respiratory System><M mulatta><M. mulatta><Macaca><Macaca mulatta><Macaque><Mature Lipocyte><Mature fat cell><Maturity-Onset Diabetes Mellitus><Mediating><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Modeling><Modern Man><Molecular><NIDDM><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Ob Gene Product><Ob Protein><Obese Gene Product><Obese Protein><Oregon><Organ><Outcome><PRSS10><Parents><Pattern><Peptidases><Peptide Hydrolases><Peptidyl-Dipeptidase A><Pharmacological Treatment><Pituitary Growth Hormone><Plasma><Plasma Serum><Primates><Primates Mammals><Protease Gene><Proteases><Proteinases><Proteins><Proteolytic Enzymes><RNA Expression><Receptor Protein><Research><Reticuloendothelial System, Serum, Plasma><Rhesus Macaque><Rhesus Monkey><Risk><Risk Factors><SARS-CoV-2><SARS-CoV2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Serine Endopeptidases><Serine Protease><Serine Protein Hydrolases><Serine Proteinases><Severe acute respiratory syndrome coronavirus 2><Severities><Severity of illness><Signal Transduction><Signal Transduction Systems><Signaling><Site><Slow-Onset Diabetes Mellitus><Somatomedin C><Somatotropin><Stable Diabetes Mellitus><Surface><Surface Proteins><Symptoms><Systems Analyses><Systems Analysis><T2 DM><T2D><T2DM><TMPRSS2><TMPRSS2 gene><Testing><Therapeutic Androgen><Therapeutic Hormone><Time><Tissues><Transcription><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Viral><Viral Diseases><Virus><Virus Diseases><Virus Replication><Weight><Wuhan coronavirus><abdominal adiposity><abdominal fat><adult onset diabetes><ages><alcohol effect><alcohol ingestion><alcohol intake><alcohol product use><alcohol use><alcoholic beverage consumption><alcoholic drink intake><allergic/immunologic body system><allergic/immunologic organ system><base><behavior study><behavioral study><biological signal transduction><bone><bone health><cardiovascular disorder><causation><co-morbid><co-morbidity><comorbidity><corona virus><corona virus disease 2019><coronavirus disease 2019><cytokine><design><designing><disease causation><disease severity><drink heavily><drinking><drinking behavior><ethanol consumption><ethanol drinking><ethanol effect><ethanol ingestion><ethanol intake><ethanol product use><ethanol use><excessive alcohol consumption><excessive alcohol ingestion><excessive alcohol intake><excessive drinking><excessive ethanol ingestion><experience><extreme drinking><heavy alcohol use><hepatic body system><hepatic organ system><high blood pressure><high risk><host response><hyperpiesia><hyperpiesis><hypertensive disease><immune modulating agents><immune modulating drug><immune modulating therapeutics><immune modulators><immune modulatory agents><immune modulatory drugs><immunomodulating agents><immunomodulatory agents><immunomodulatory drugs><immunomodulatory therapeutics><immunoresponse><infection risk><insight><ketosis resistant diabetes><life-style factor><lifestyle factors><male><maturity onset diabetes><non-human primate><nonhuman primate><off-label application><off-label prescribing><off-label use><protein expression><pulmonary><receptor><response><sex><somatotropic hormone><type 2 DM><type II DM><type two diabetes><viral infection><viral multiplication><viral replication><virus infection><virus multiplication><virus-induced disease>