Extracellular vesicle‐mediated endothelial apoptosis and EV‐associated proteins correlate with COVID‐19 disease severity

  1. Balaji Krishnamachary
  2. Christine Cook
  3. Ashok Kumar
  4. Leslie Spikes
  5. Prabhakar Chalise
  6. Navneet K. Dhillon

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Abstract

Coronavirus disease‐2019 (COVID‐19), caused by the novel severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), has lead to a global pandemic with a rising toll in infections and deaths. Better understanding of its pathogenesis will greatly improve the outcomes and treatment of 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 with different stages of disease severity. Our findings reveal significant enrichment of proinflammatory, procoagulation, immunoregulatory and tissue‐remodelling protein signatures in EVs, which remarkably distinguished symptomatic COVID‐19 patients from uninfected controls with matched comorbidities and delineated those with moderate disease from those who were critically 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 apoptosis of pulmonary microvascular endothelial cells in the order of disease severity. In conclusion, our findings support a role for EVs in the pathogenesis of COVID‐19 disease and underpin the development of EV‐based approaches to predicting disease severity, determining need for patient hospitalization and identifying new therapeutic targets.

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  1. Version published to 10.1002/jev2.12117
  2. ScreenIT

    SciScore for 10.1101/2020.08.27.20182808: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementConsent: Written informed consent for participation in the Biorepository was obtained from all patients or their surrogates.
    IRB: This study and the COVID-19 Biorepository were approved by the University of Kansas Medical Center Institutional Review Board.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    While our results show multiple, promising insights into the pathophysiology of COVID-19 infection and the potential role of circulating EVS in the related immune response, our study does have some limitations. We were limited in the number of healthy controls available to compare against our four infected groups. The healthy samples we were able to obtain were not drawn under the same conditions as those enrolled in the biorepository, such as a fasting condition or time of day. We also lacked an uninfected control group with similar comorbidities, including hypertension and diabetes. Overall, our samples sizes were relatively small, and future analysis using larger cohorts is warranted. Furthermore, in addition to LEVs, significantly increased circulating small EVs in severe COVID-19 patients are also believed to play an important role in pathogenesis and analysis of SEV cargo is currently part of our ongoing studies. In conclusion, this unique study contributes to the expanding knowledge of the pathophysiology of this highly infectious and devastating disease. We suggest that large extracellular vesicles play a significant role in COVID-19 patients by contributing to the augmented pro-inflammatory response, endothelial dysfunction and micro-thrombosis observed in patients who have more severe disease. Perhaps this knowledge around EVs will contribute to determining potential biomarkers for poorer outcomes in COVID-19 infection and offer a novel way to approach therapies to ...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  3. Version published to 10.1101/2020.08.27.20182808 on medRxiv