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

Abstract

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.

Authors: Knoll R, Helbig ET, Dahm K, Bolaji O, Hamm F, Dietrich O, van Uelft M, Müller S, Bonaguro L, Schulte-Schrepping J, Petrov L, Krämer B, Kraut M, Stubbemann P, Thibeault C, Brumhard S, Theis H, Hack G, De Domenico E, Nattermann J, Becker M
Journal: Cell . 2024 Aug 8;187(16):4318-4335.e20. doi:10.1016/j.cell.2024.06.014
Year: 2024
PubMed: PMID: 38964327 (Go to PubMed)