COVID19: HDL’s Role in Innate Immunity and Cardiovascular Protection with COVID-19 The novel coronavirus (SARS-CoV-2) causes a disease called COVID-19. For many people, COVID-19 has almost no symptoms, yet for others, COVID-19 is particularly dangerous and has high morbidity and mortality rates. People with pre-existing type-2 diabetes and atherosclerotic cardiovascular disease (ASCVD) have twice the risk of SARS-CoV-2 infection and are more likely to have poor outcomes. 70% of patients with ASCVD and elevated troponin die of COVID. We don’t know what intrinsic factors contribute to these disparate outcomes. High Density Lipoprotein (HDL) particles play a critical role in the innate immune system and are protective against viral and bacterial infections. HDL particles best are known for their roles protecting from atherosclerotic cardiovascular disease (ASCVD). The cardiovascular protection conferred by HDL is largely mediated by HDL’s associated proteins, which comprise about half of HDL’s mass. Mechanisms for HDL’s protection from ASCVD are shared with mechanisms for HDL’s protection from viral infections. These protective properties center around the HDL-associated proteins that mediate its anti-inflammatory and antioxidative functions. The goal of this project is to define how HDL may protect from Sars-CoV-2 infection and limit the inflammatory response to COVID-19 illness. Obesity and type-2 diabetes (DM2) lead to hypertriglyceridemia and metabolic changes that impair HDL’s anti-inflammatory and antioxidative functions. We will define if DM2 leads to HDL dysfunction and contributes to severe COVID-19 outcomes. Our overarching hypothesis is that HDL’s antiviral properties can limit SARS-CoV-2 infection and that HDL’s anti-inflammatory and antioxidative capacity limit the systemic inflammatory response to COVID-19. We have initiated a collaboration with Dr. Malall, an immunology expert running a large trial with COVID-19 patients whose de-identified samples are paired with de-identified EMR outcomes data. In AIM1 we will test the hypothesis that SARS-CoV-2 infection impairs HDL’s antioxidative and anti-inflammatory capacities, and that these changes can be predicted by proteomic signatures of HDL. We also have collaboration with Dr. Denison, an expert in coronavirus biology. In AIM2 we will test the hypothesis that HDL can reduce SARS-CoV-2 infectivity of lung epithelial cells, but that COVID-19 impairs HDL’s antiviral capacity, which can be improved with Remdesavir treatment. In AIM3 we will test the hypothesis that type-2 diabetes alters the HDL-associated protein networks that limit systemic inflammation with COVID-19 and protect against SARS-CoV-2 infection. Diabetes and cardiovascular disease are among the most prevalent problems among United States Veterans, making Veterans more likely to have poor COVID-19 outcomes. An asset to this project is that we can relate our HDL function and antiviral assays with clinical outcomes. Our studi...