Extracellular vesicle-mediated endothelial apoptosis

Coronavirus disease 2019 (COVID-19), caused by the new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has led to a global pandemic with an increasing number of infections and deaths. A better understanding of its pathogenesis will greatly improve outcomes and treatment for affected patients. Here, we compared the inflammatory and cardiovascular disease-related protein cargo of circulating large and small extracellular vesicles (EVs) from 84 hospitalized patients infected with SARS-CoV-2 at different stages of disease severity.

Our results reveal significant enrichment of pro-inflammatory, procoagulation, immunoregulatory, and tissue remodeling protein signatures in EVs, which remarkably distinguish symptomatic COVID-19 patients from uninfected controls with matched comorbidities and delineate those with disease. moderate in those who were seriously ill.

Specifically, EN-RAGE, followed by TF and IL-18R1, showed the strongest correlation with disease severity and length of hospitalization. Importantly, EVs from COVID-19 patients induced lung microvascular endothelial cell apoptosis in the order of disease severity. In conclusion, our results support the role of EVs in the pathogenesis of COVID-19 disease and underpin the development of EV-based approaches to predict disease severity, determine the need for patient hospitalization, and identify novel therapeutic targets.

Coronavirus disease-2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) (WCDC Dashboard- 2020; Wu et al., 2020) is marked by endothelial dysfunction and responses dysregulated immune systems (Huertas et al., 2020). Like the SARS-CoV pathogen that led to outbreaks in 2002 and 2003, SARS-CoV-2 enters cells via binding of its spike protein to angiotensin-converting enzyme 2 receptors (ACE2).

ACE2 receptors are abundantly present in lung alveolar type II and endothelial cells, making the lungs and pulmonary vasculature susceptible to SARS-CoV-2-induced inflammation and injury (Zhao et al., 2020) . Additionally, alveolar capillary micro-thrombus and endothelial lesions with evidence of intracellular virus were noted during post-mortem analysis of infected lungs (Ackermann et al., 2020).

Although there is growing evidence that endothelial damage, vascular remodeling and coagulopathy are the main consequences of COVID-19 infection, it remains unclear how the virus induces these changes. Extracellular vesicles (EVs) carry proteins, coding and non-coding RNA, DNA fragments and lipids, which facilitate crosstalk between cells.

VE cargo transfer plays an important role in a number of disease processes, including cardiovascular disease, pulmonary hypertension, and various malignancies (Jansen et al., 2017; Meldolesi, 2019). EVs can be released in response to thrombin, shear stress, complement activation, and inflammation, among other pathophysiological triggers.

Not only can EVs mediate disease through cellular interference, but their cargo can also serve as biomarkers of disease state. Sequence analysis of EV content can provide snapshots of disease progression over time (Urabe et al., 2020). In this study, we analyzed alterations in plasma-derived EVs from SARS-CoV-2 infected patients to investigate the role(s) that EVs may play in the pathophysiology of COVID-19 disease and to identify potential biomarkers of COVID-19 disease severity and progression.