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.

PROJECT NARRATIVE SARS-CoV-2, the viral cause of Coronavirus Disease 2019 (COVID-19), is a highly contagious virus that results in severe disease in 20% of infected individuals. 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 in a non-human primate model for voluntary drinking that mimics the full range of human drinking behavior. The research will also help identify potential interactions between alcohol consumption and factors such as sex, age and weight in influencing COVID-19 outcome.