Effect of Alcohol Consumption on Molecular Risk Factors for SARS-CoV-2

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 andother organs, including liver and immune system, with non-lung infections contributing to the etiology of severeCOVID-19. Co-morbidity factors associated with poorer health outcomes include male sex, older age, anddisease. However, these do not fully explain the distribution of COVID-19 severity, suggesting additionalmodifying factors. Based on the molecular mechanisms mediating viral infection, excessive alcoholconsumption may be an unrecognized factor influencing SARS-CoV-2 infection. Spike proteins on the surfaceof SARS-CoV-2, and host serine proteases (such as furin and TMPRSS2) and ACE2-expressing receptor siteson target cells are required for SARS-CoV-2 infection. Conversely, ADAM17 (TACE), a major sheddase ofACE2, may lower infection. There is strong circumstantial evidence that alcohol directly increases risk forCOVID-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 knownregulator of TMPRSS2 gene transcription, suggesting a plausible mechanism for male sex as a risk factor forsevere COVID-19. Additionally, alcohol lowers ADAM17 levels and increases levels of the adipocyte-derivedhormone leptin; Adam17 and leptin are important modulators of immune response to viral infection. Based onthe literature and preliminary data, we hypothesize alcohol consumption results in undesirable levels of plasmaand 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 - onprotein 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 maleand female rhesus macaques. The macaques were subjected to voluntary alcohol intake that mimics the fullrange of human drinking behavior (www.MATRR.com). The proposed research will provide insight into alcoholconsumption as a potential life-style factor for increasing risk for infection by SARS-CoV-2 and contributing topoorer health outcomes following infection. The research will also help identify potential interactions betweenalcohol consumption and intrinsic factors such as sex, age and weight in influencing COVID-19 outcome. Therequested supplement is a logical extension of the parent proposal (R01AA026289: Complex SystemsAnalysis of the Impact of Alcohol on Bone in Non-Human Primates) designed to: (1) determine the contributionof invariant intrinsic factors (e.g., age, sex, species) and variable extrinsic factors (e.g., drinking pattern) onorgan effects of alcohol (original focus on bone), and (2) identify the contribution of hormones/cytokines.