Journal Article

DZNE-2024-01024

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The life-saving benefit of dexamethasone in severe COVID-19 is linked to a reversal of monocyte dysregulation.

Knoll, R. (First author)DZNE* ; Helbig, E. T. ; Dahm, K.DZNE* ; Bolaji, O. ; Hamm, F. ; Dietrich, O. ; van Uelft, M.DZNE* ; Müller, S.DZNE* ; Bonaguro, L.DZNE* ; Schulte-Schrepping, J.DZNE* ; Petrov, L. ; Krämer, B. ; Kraut, M.DZNE* ; Stubbemann, P. ; Thibeault, C. ; Brumhard, S. ; Theis, H.DZNE* ; Hack, G. ; De Domenico, E.DZNE* ; Nattermann, J. ; Becker, M.DZNE* ; Beyer, M. D.DZNE* ; Hillus, D. ; Georg, P. ; Loers, C. ; Tiedemann, J. ; Tober-Lau, P. ; Lippert, L. ; Millet Pascual-Leone, B. ; Tacke, F. ; Rohde, G. ; Suttorp, N. ; Witzenrath, M. ; Group, C. S. (Collaboration Author) ; Group, P. S. (Collaboration Author) ; Saliba, A.-E. ; Ulas, T.DZNE* ; Polansky, J. K. ; Sawitzki, B. ; Sander, L. E. ; Schultze, J. L.DZNE* ; Aschenbrenner, A. C.DZNE* ; Kurth, F.

2024
Elsevier New York, NY

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Please use a persistent id in citations: doi:10.1016/j.cell.2024.06.014

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.

Keyword(s): Humans (MeSH) ; Dexamethasone: pharmacology (MeSH) ; Dexamethasone: therapeutic use (MeSH) ; Monocytes: metabolism (MeSH) ; Monocytes: drug effects (MeSH) ; COVID-19 Drug Treatment (MeSH) ; COVID-19 (MeSH) ; SARS-CoV-2: drug effects (MeSH) ; Male (MeSH) ; Single-Cell Analysis (MeSH) ; Female (MeSH) ; Transcriptome (MeSH) ; Middle Aged (MeSH) ; Aged (MeSH) ; Glucocorticoids: therapeutic use (MeSH) ; Glucocorticoids: pharmacology (MeSH) ; Lung: pathology (MeSH) ; Adult (MeSH) ; COVID-19 ; companion diagnostics ; glucocorticoid ; in vivo target engagement ; monocytes ; single-cell analysis ; transcriptomics ; treatment response prediction ; Dexamethasone ; Glucocorticoids

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Contributing Institute(s):

1. Aging and Immunity (AG Aschenbrenner)
2. Clinical Single Cell Omics (CSCO) / Systems Medicine (AG Schultze)
3. Modular High Performance Computing and Artificial Intelligence (AG Becker)
4. Immunogenomics and Neurodegeneration (AG Beyer)
5. Platform for Single Cell Genomics and Epigenomics (PRECISE)

Research Program(s):

1. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)
2. 351 - Brain Function (POF4-351) (POF4-351)
3. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Experiment(s):

1. Platform for Single Cell Genomics and Epigenomics at DZNE University of Bonn

Appears in the scientific report 2024

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 60 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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