The life-saving benefit of dexamethasone in severe COVID-19 is linked to a reversal of monocyte dysregulation
Authors:
- Knoll, Rainer
- Helbig, Elisa T.
- Dahm, Kilian
- Bolaji, Olufemi
- Hamm, Frederik
- Dietrich, Oliver
- van Uelft, Martina
- Müller, Sophie
- Bonaguro, Lorenzo
- Schulte-Schrepping, Jonas
- Petrov, Lev
- Krämer, Benjamin
- Kraut, Michael
- Stubbemann, Paula
- Thibeault, Charlotte
- Brumhard, Sophia
- Theis, Heidi
- Hack, Gudrun
- De Domenico, Elena
- Nattermann, Jacob
- Becker, Matthias
- Beyer, Marc D.
- Hillus, David
- Georg, Philipp
- Loers, Constantin
- Tiedemann, Janina
- Tober-Lau, Pinkus
- Lippert, Lena
- Millet Pascual-Leone, Belén
- Tacke, Frank
- Rohde, Gernot
- Suttorp, Norbert
- Witzenrath, Martin
- Saliba, Antoine-Emmanuel
- Ulas, Thomas
- Polansky, Julia K.
- Sawitzki, Birgit
- Sander, Leif E.
- Schultze, Joachim L.
- Aschenbrenner, Anna C.
- Kurth, Florian
Details:
Cell, Volume 187, Issue 16, 2024-08-08
Article Link: Click here
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.