Serum proteomics hint at an early T-cell response and modulation of SARS-CoV-2-related pathogenic pathways in COVID-19-ARDS treated with Ruxolitinib

Sara Völkel; Thomas S Tarawneh; Laura Sacher; Aditya M Bhagwat; Ihab Karim; Hildegard I D Mack; Thomas Wiesmann; Björn Beutel; Joachim Hoyer; Christian Keller; Harald Renz; Andreas Burchert; Andreas Neubauer; Johannes Graumann; Chrysanthi Skevaki; Elisabeth K M Mack

doi:10.3389/fmed.2023.1176427

Serum proteomics hint at an early T-cell response and modulation of SARS-CoV-2-related pathogenic pathways in COVID-19-ARDS treated with Ruxolitinib

Front Med (Lausanne). 2023 May 24:10:1176427. doi: 10.3389/fmed.2023.1176427. eCollection 2023.

Authors

Sara Völkel^#¹, Thomas S Tarawneh^#², Laura Sacher¹, Aditya M Bhagwat³, Ihab Karim², Hildegard I D Mack⁴, Thomas Wiesmann^{5

6}, Björn Beutel^{7

8}, Joachim Hoyer⁹, Christian Keller¹⁰, Harald Renz^{1

8}, Andreas Burchert², Andreas Neubauer², Johannes Graumann^{3

11}, Chrysanthi Skevaki^{1

8}, Elisabeth K M Mack²

Affiliations

¹ Institute of Laboratory Medicine, Philipps-University Marburg, Marburg, Germany.
² Department of Hematology, Oncology and Immunology, University Hospital Gießen and Marburg, Philipps-University Marburg, Marburg, Germany.
³ Institute of Translational Proteomics, Philipps-University Marburg, Marburg, Germany.
⁴ Institute for Biomedical Aging Research, Leopold-Franzens-Universität Innsbruck, Innsbruck, Austria.
⁵ Department of Anesthesiology and Intensive Care Medicine, University Hospital Gießen and Marburg, Philipps-University Marburg, Marburg, Germany.
⁶ Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, Diakonie-Klinikum Schwäbisch Hall, Schwäbisch Hall, Germany.
⁷ Department of Pulmonary and Critical Care Medicine, University Hospital Gießen and Marburg, Philipps-University Marburg, Marburg, Germany.
⁸ German Center for Lung Research (DZL), Member of the Universities of Gießen and Marburg Lung Center, Gießen, Germany.
⁹ Department of Nephrology, University Hospital Gießen and Marburg, Philipps-University Marburg, Marburg, Germany.
¹⁰ Institute of Virology, Philipps-University Marburg, Marburg, Germany.
¹¹ Biomolecular Mass Spectrometry, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.

^# Contributed equally.

Abstract

Background: Acute respiratory distress syndrome (ARDS) in corona virus disease 19 (COVID-19) is triggered by hyperinflammation, thus providing a rationale for immunosuppressive treatments. The Janus kinase inhibitor Ruxolitinib (Ruxo) has shown efficacy in severe and critical COVID-19. In this study, we hypothesized that Ruxo's mode of action in this condition is reflected by changes in the peripheral blood proteome.

Methods: This study included 11 COVID-19 patients, who were treated at our center's Intensive Care Unit (ICU). All patients received standard-of-care treatment and n = 8 patients with ARDS received Ruxo in addition. Blood samples were collected before (day 0) and on days 1, 6, and 10 of Ruxo treatment or, respectively, ICU admission. Serum proteomes were analyzed by mass spectrometry (MS) and cytometric bead array.

Results: Linear modeling of MS data yielded 27 significantly differentially regulated proteins on day 1, 69 on day 6 and 72 on day 10. Only five factors (IGLV10-54, PSMB1, PGLYRP1, APOA5, WARS1) were regulated both concordantly and significantly over time. Overrepresentation analysis revealed biological processes involving T-cells only on day 1, while a humoral immune response and complement activation were detected at day 6 and day 10. Pathway enrichment analysis identified the NRF2-pathway early under Ruxo treatment and Network map of SARS-CoV-2 signaling and Statin inhibition of cholesterol production at later time points.

Conclusion: Our results indicate that the mechanism of action of Ruxo in COVID-19-ARDS can be related to both known effects of this drug as a modulator of T-cells and the SARS-CoV-2-infection.

Keywords: COVID-19; Ruxolitinib; SARS-CoV-2; acute respiratory distress syndrome; proteomics.

Grants and funding

CS was supported by the Universities of Gießen and Marburg Lung Center (UGMLC), the German Center for Lung Research (DZL), University Hospital Gießen and Marburg (UKGM) research funding according to article 2, section 3 cooperation agreement, and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)-Project-ID 197785619 – SFB 1021, KFO 309 (Project Number: 284237345), and SK 317/1-1 (Project Number: 428518790) as well as by the Foundation for Pathobiochemistry and Molecular Diagnostics. EM was supported by the Clinician Scientist Program and the Research Foundation of the Faculty of Medicine, Philipps-University Marburg. SV received an early career support grant from the German Research Foundation (KFO 309). HM was supported by Foundation Daniel Swarovski. AN was funded by the Deutsche José-Carreras Leukämie-Stiftung (Grant Number: AH 06-01) and also received funding for the RuXoCoil trial from Novartis pharma. Open access funding was provided by the Open Acess Publishing Fund of Philipps-University Marburg with support of the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation). Novartis pharma was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.