The Potential Role of Extracellular Vesicles in COVID-19 Associated Endothelial injury and Pro-inflammation

Abstract

COVID-19 infection caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in a global pandemic with the number of deaths growing exponentially. Early evidence points to significant endothelial dysfunction, micro-thromboses, pro-inflammation as well as a dysregulated immune response in the pathogenesis of this disease. In this study, we analyzed the cargo of 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. Plasma-derived EVs were isolated from 53 hospitalized patients with COVID infection and compared according to the severity of the disease. Analysis of inflammatory and cardiovascular protein cargo of large EVs revealed significantly differentially expressed proteins for each disease sub-group. Notably, members of the TNF superfamily and IL-6 family were up-regulated in patients on oxygen support with severe and moderate disease. EVs from the severe group were also enhanced with pro-thrombotic/endothelial injury factors (TF, t-PA, vWF) and proteins associated with cardiovascular pathology (MB, PRSS8, REN, HGF). Significantly higher levels of TF, CD163, and EN-RAGE were observed in EVs from severe patients when compared to patients with a moderate disease requiring supplemental O2. Importantly, we also observed increased caspase 3/7 activity and decreased cell survival in human pulmonary microvascular endothelial cells exposed to EVs from the plasma of patients with severe disease compared to healthy controls. In conclusion, our findings indicate alterations in pro-inflammatory, coagulopathy, and endothelial injury protein cargo in large EVs in response to SARS-CoV-2 infection that may be a causative agent in severe illness.

Journey to a Receptor for Advanced Glycation End Products Connection in Severe Acute Respiratory Syndrome Coronavirus 2 Infection

“… 42 Fourth, in extracellular vesicles, significantly higher levels of S100A12 were observed in patients with severe versus moderate COVID-19. 43 Fifth, higher levels of S100A8/A9 and a distinct DAMP RAGE ligand, HMGB1, were found to associate with higher risk of intensive care unit admission and death in patients with COVID-19. 44 Sixth, HMGB1 was reported to induce NETosis (neutrophil extracellular traps) 45 and to induce ACE2 expression, critical for SARS-CoV-2 entry into cells.…”

Pulmonary Endothelial Dysfunction and Thrombotic Complications in Patients with COVID-19

“…Endothelial EVs are particles naturally released from ECs contained by a lipid bilayer and carry coding and noncoding RNA, proteins, DNA fragments, and lipids, which facilitate cell–cell communication ( 12 , 13 ). An increased number of endothelial EVs has been reported in a variety of vascularly related disorders ( 14 , 15 ), and their amounts inversely correlated with endothelial function ( 11 ).…”

“…An increased number of endothelial EVs has been reported in a variety of vascularly related disorders ( 14 , 15 ), and their amounts inversely correlated with endothelial function ( 11 ). A recent study reported that EVs isolated from the plasma of patients with COVID-19 carried high concentration of proinflammatory cytokines, proteases, and peptidases, which correlated with disease severity ( 12 ). This suggests that EVs could be important players in COVID-19 pathophysiology and disease progression.…”

Investigation of Extracellular Vesicles From SARS-CoV-2 Infected Specimens: A Safety Perspective

“…More recently, Cappellano and collaborators reported that platelet EVs, quantified by CD31 and CD41 flow cytometry on 2 independent cohorts in Italy, were significantly elevated in hospitalized patients, as compared to healthy controls. Importantly, a proteomics profiling study of large EVs isolated from 53 hospitalized COVID-19 patients in China, found that alterations in pro-inflammatory, coagulation, and endothelial injury protein cargo in the large EVs may contribute to severe COVID-19 (30). On the other hand, Yu and collaborators reported that pseudotyped SARS-CoV-2 and HIV-based lentivirus induces the production of EVs with adaptive immunity-like antiviral functions in murine hypothalamic neural stem cells (31).…”