Circulating endothelial extracellular vesicle signatures correspond with ICU requirement: an exploratory study in COVID-19 patients

Johannes Zipperle; Johannes Oesterreicher; Matthias Hackl; Teresa Lara Krammer; Helena Thumfart; Madhusudhan Reddy Bobbili; Marion Wiegele; Johannes Grillari; Marcin F Osuchowski; Herbert Schöchl; Wolfgang Holnthoner; Christoph J Schlimp; Judith Schiefer; Marco Valerio Pesce; Stefan Ulbing; Johannes Gratz

doi:10.1186/s40635-023-00567-7

Circulating endothelial extracellular vesicle signatures correspond with ICU requirement: an exploratory study in COVID-19 patients

Intensive Care Med Exp. 2023 Nov 30;11(1):85. doi: 10.1186/s40635-023-00567-7.

Authors

Johannes Zipperle¹, Johannes Oesterreicher^{2

3}, Matthias Hackl^{3

4}, Teresa Lara Krammer⁴, Helena Thumfart², Madhusudhan Reddy Bobbili^{2

3

5}, Marion Wiegele⁶, Johannes Grillari^{2

3

5}, Marcin F Osuchowski², Herbert Schöchl^{2

7}, Wolfgang Holnthoner^{2

3}, Christoph J Schlimp^{2

8}, Judith Schiefer⁶, Marco Valerio Pesce⁶, Stefan Ulbing^{6

9}, Johannes Gratz⁶

Affiliations

¹ Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation With AUVA, Vienna, Austria. Johannes.zipperle@trauma.lbg.ac.at.
² Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation With AUVA, Vienna, Austria.
³ Austrian Cluster for Tissue Regeneration, Vienna, Austria.
⁴ TAmiRNA GmbH, Vienna, Austria.
⁵ Institute for Molecular Biotechnology, Department for Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria.
⁶ Department of Anaesthesia, Intensive Care Medicine and Pain Medicine, Medical University of Vienna, Vienna, Austria.
⁷ AUVA Trauma Center Salzburg, Department of Anaesthesiology and Intensive Care Medicine, Academic Teaching Hospital of the Paracelsus Medical University, Salzburg, Austria.
⁸ Department of Anaesthesiology and Intensive Care Medicine, AUVA Trauma Center Linz, Linz, Austria.
⁹ Ludwig Boltzmann Institute Digital Health and Patient Safety, Vienna, Austria.

Abstract

Extracellular vesicles (EVs) represent nanometer-sized, subcellular spheres, that are released from almost any cell type and carry a wide variety of biologically relevant cargo. In severe cases of coronavirus disease 2019 (COVID-19) and other states of systemic pro-inflammatory activation, EVs, and their cargo can serve as conveyors and indicators for disease severity and progression. This information may help distinguish individuals with a less severe manifestation of the disease from patients who exhibit severe acute respiratory distress syndrome (ARDS) and require intensive care measures. Here, we investigated the potential of EVs and associated miRNAs to distinguish normal ward patients from intensive care unit (ICU) patients (N = 10/group), with 10 healthy donors serving as the control group. Blood samples from which plasma and subsequently EVs were harvested by differential ultracentrifugation (UC) were obtained at several points in time throughout treatment. EV-enriched fractions were characterized by flow cytometry (FC), nanoparticle tracking analysis (NTA), and qPCR to determine the presence of selected miRNAs. Circulating EVs showed specific protein signatures associated with endothelial and platelet origin over the course of the treatment. Additionally, significantly higher overall EV quantities corresponded with increased COVID-19 severity. MiR-223-3p, miR-191-5p, and miR-126-3p exhibited higher relative expression in the ICU group. Furthermore, EVs presenting endothelial-like protein signatures and the associated miR-126-3p showed the highest area under the curve in terms of receiver operating characteristics regarding the requirement for ICU treatment. In this exploratory investigation, we report that specific circulating EVs and miRNAs appear at higher levels in COVID-19 patients, especially when critical care measures are indicated. Our data suggest that endothelial-like EVs and associated miRNAs likely represent targets for future laboratory assays and may aid in clinical decision-making in COVID-19.

Keywords: Biomarker; COVID-19; Critical care medicine; Extracellular vesicles; Intensive care unit; SARS-CoV-2; miRNAs.