Purinergic modulation of the autoimmune vascular phenotype

ABSTRACTThis Coronavirus Disease 2019 (COVID-19) supplement will study the role of neutrophil extracellular traps(NETs) as biomarkers and therapeutic targets in COVID-19. The supplement will preserve the parent project'sfocus on ectoenzymes and purinergic signaling as amplifiable counterpoints to neutrophil hyperactivity andexaggerated NET release (NETosis). Indeed, elevated levels of blood neutrophils are an early indicator ofSARS-CoV-2 infection, where they predict severe COVID-19 respiratory disease.Our group and others have recently revealed a critical role for NETs in various thrombo-inflammatory statesincluding sepsis, venous thrombosis, and respiratory failure. NETs are extracellular tangles of chromatin,microbicidal proteins, and oxidant enzymes that are released by neutrophils to corral infections; however, whennot properly regulated, NETs have potential to amplify inflammation and thrombosis. In COVID-19, wehypothesize that NETs will function as powerful biomarkers for predicting progression to respiratory failure.With special relevance to this application, a recent study performed in China suggested potential efficacy of theadenosine-receptor agonist, dipyridamole in severe cases of COVID-19. Dipyridamole is an FDA-approveddrug that our group recently discovered-through work on the parent project-to inhibit NETosis via activationof adenosine A2A receptors (A2AR). The hypothesis here is that A2AR agonists such as dipyridamole willcompensate for virus-mediated deficiencies in the pulmonary ACE2 axis and thereby suppress NETosis.This supplement requests funds to support three complementary Aims. Aim 1 will determine the extent towhich NET levels can be used as predictive biomarkers in COVID-19. Aim 2 will elucidate mechanisms bywhich the ACE2/angiotensin-(1-7) axis regulates COVID-19 neutrophils. Finally, Aim 3 will determine theextent to which adenosine receptor agonism prevents NETosis and macrophage activation in COVID-19.