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The life-saving benefit of dexamethasone in severe COVID-19 is linked to a reversal of monocyte dysregulation.


Authors: Rainer Knoll, Elisa T Helbig, Kilian Dahm, Olufemi Bolaji, Frederik Hamm, Oliver Dietrich, Martina van Uelft, Sophie Müller, Lorenzo Bonaguro, Jonas Schulte-Schrepping, Lev Petrov, Benjamin Krämer, Michael Kraut, Paula Stubbemann, Charlotte Thibeault, Sophia Brumhard, Heidi Theis, Gudrun Hack, Elena De Domenico, Jacob Nattermann, Matthias Becker, Marc D Beyer, David Hillus, Philipp Georg, Constantin Loers, Janina Tiedemann, Pinkus Tober-Lau, Lena Lippert, Belén Millet Pascual-Leone, Frank Tacke, Gernot Rohde, Norbert Suttorp, Martin Witzenrath, Antoine-Emmanuel Saliba, Thomas Ulas, Julia K Polansky, Birgit Sawitzki, Leif E Sander, Joachim L Schultze, Anna C Aschenbrenner, Florian Kurth

Dexamethasone is a life-saving treatment for severe COVID-19, yet its mechanism of action is unknown, and many patients deteriorate or die despite timely treatment initiation. Here, we identify dexamethasone treatment-induced cellular and molecular changes associated with improved survival in COVID-19 patients. We observed a reversal of transcriptional hallmark signatures in monocytes associated with severe COVID-19 and the induction of a monocyte substate characterized by the expression of glucocorticoid-response genes. These molecular responses to dexamethasone were detected in circulating and pulmonary monocytes, and they were directly linked to survival. Monocyte single-cell RNA sequencing (scRNA-seq)-derived signatures were enriched in whole blood transcriptomes of patients with fatal outcome in two independent cohorts, highlighting the potential for identifying non-responders refractory to dexamethasone. Our findings link the effects of dexamethasone to specific immunomodulation and reversal of monocyte dysregulation, and they highlight the potential of single-cell omics for monitoring in vivo target engagement of immunomodulatory drugs and for patient stratification for precision medicine approaches.

Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

PMID: 38964327

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