ABSTRACT
It is increasingly recognized that moderate/severe coronavirus disease 2019 (COVID-19) disease is in part due to a dysregulated immune response in conjunction with increased thromboinflammation, coagulopathy, and vascular injury. In this study, we analyzed the cargo of extracellular vesicles (EVs) isolated from the plasma of patients with COVID-19 for the identification of potential biomarkers of disease severity and to explore their role in disease pathogenesis. Severe acute respiratory syndrome coronavirus 2-infected patients hospitalized at the University of Kansas Health System were enrolled in the COVID-19 In-patient Biorepository and blood samples were collected for the isolation of plasmaderived EVs. The patients were grouped based on the WHO Clinical Progression Scale score during hospitalization. Our results revealed enrichment of proinflammatory, procoagulation, and tissue-remodeling markers in circulating EVs, distinguishing symptomatic COVID-19 patients from uninfected controls and delineating patients with moderate disease from the critically ill. Among all proteins analyzed, the levels of proinflammatory DAMP: EN-RAGE (aka calgranulin C or S100A12) showed the strongest correlation with length of hospitalization and disease severity. In addition, tissue factor levels/activity linked to EVs appeared to distinguish patients with severe disease from those with a moderate disease but on supplemental oxygen. Alterations in EV cargo corresponded to enhanced apoptosis of primary human pulmonary microvascular endothelial cells and smooth muscle hyperplasia on exposure to EVs from COVID-19 patients. In conclusion, our findings suggest a pivotal role of EVs in the pathogenesis of acute COVID-19 disease. Whether these EV-mediated alterations continue leading to long-haul COVID including cardiopulmonary vascular complications is the focus of our ongoing studies.