Key benefits of dexamethasone and antibody treatment in COVID-19 hamster models revealed by single-cell transcriptomics.

Autor:	Wyler E; Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. Electronic address: emanuel.wyler@mdc-berlin.de., Adler JM; Institute of Virology, Freie Universität Berlin, Berlin, Germany; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Division of Pulmonary Inflammation, Berlin, Germany., Eschke K; Institute of Virology, Freie Universität Berlin, Berlin, Germany., Teixeira Alves G; Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany., Peidli S; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Berlin, Germany; IRI Life Sciences, Institute for Biology, Humboldt-Universität zu Berlin, Berlin, Germany., Pott F; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Virology, Berlin, Germany; Berlin Institute of Health (BIH), Berlin, Germany., Kazmierski J; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Virology, Berlin, Germany; Berlin Institute of Health (BIH), Berlin, Germany., Michalick L; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Physiology, Berlin, Germany., Kershaw O; Institute of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany., Bushe J; Institute of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany., Andreotti S; Bioinformatics Solution Center, Freie Universität Berlin, Berlin, Germany., Pennitz P; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Division of Pulmonary Inflammation, Berlin, Germany; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Infectious Diseases and Respiratory Medicine, Berlin, Germany., Abdelgawad A; Institute of Virology, Freie Universität Berlin, Berlin, Germany., Postmus D; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Virology, Berlin, Germany; Berlin Institute of Health (BIH), Berlin, Germany., Goffinet C; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Virology, Berlin, Germany; Berlin Institute of Health (BIH), Berlin, Germany., Kreye J; German Center for Neurodegenerative Diseases (DZNE) Berlin, Helmholtz Innovation Lab BaoBab (Brain Antibody-Omics and B-Cell Lab), Berlin, Germany; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neurology and Experimental Neurology, Berlin, Germany; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Neurology, Berlin, Germany., Reincke SM; German Center for Neurodegenerative Diseases (DZNE) Berlin, Helmholtz Innovation Lab BaoBab (Brain Antibody-Omics and B-Cell Lab), Berlin, Germany; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neurology and Experimental Neurology, Berlin, Germany., Prüss H; German Center for Neurodegenerative Diseases (DZNE) Berlin, Helmholtz Innovation Lab BaoBab (Brain Antibody-Omics and B-Cell Lab), Berlin, Germany; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neurology and Experimental Neurology, Berlin, Germany., Blüthgen N; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Berlin, Germany; IRI Life Sciences, Institute for Biology, Humboldt-Universität zu Berlin, Berlin, Germany., Gruber AD; Institute of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany., Kuebler WM; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Physiology, Berlin, Germany., Witzenrath M; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Division of Pulmonary Inflammation, Berlin, Germany; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Infectious Diseases and Respiratory Medicine, Berlin, Germany., Landthaler M; Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany; IRI Life Sciences, Institute for Biology, Humboldt-Universität zu Berlin, Berlin, Germany., Nouailles G; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Division of Pulmonary Inflammation, Berlin, Germany. Electronic address: geraldine.nouailles@charite.de., Trimpert J; Institute of Virology, Freie Universität Berlin, Berlin, Germany. Electronic address: trimpert.jakob@fu-berlin.de.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2022 May 04; Vol. 30 (5), pp. 1952-1965. Date of Electronic Publication: 2022 Mar 24.
DOI:	10.1016/j.ymthe.2022.03.014
Abstrakt:	For coronavirus disease 2019 (COVID-19), effective and well-understood treatment options are still scarce. Since vaccine efficacy is challenged by novel variants, short-lasting immunity, and vaccine hesitancy, understanding and optimizing therapeutic options remains essential. We aimed at better understanding the effects of two standard-of-care drugs, dexamethasone and anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies, on infection and host responses. By using two COVID-19 hamster models, pulmonary immune responses were analyzed to characterize effects of single or combinatorial treatments. Pulmonary viral burden was reduced by anti-SARS-CoV-2 antibody treatment and unaltered or increased by dexamethasone alone. Dexamethasone exhibited strong anti-inflammatory effects and prevented fulminant disease in a severe disease model. Combination therapy showed additive benefits with both anti-viral and anti-inflammatory potency. Bulk and single-cell transcriptomic analyses confirmed dampened inflammatory cell recruitment into lungs upon dexamethasone treatment and identified a specifically responsive subpopulation of neutrophils, thereby indicating a potential mechanism of action. Our analyses confirm the anti-inflammatory properties of dexamethasone and suggest possible mechanisms, validate anti-viral effects of anti-SARS-CoV-2 antibody treatment, and reveal synergistic effects of a combination therapy, thus informing more effective COVID-19 therapies. Competing Interests: Declaration of interests Related to this work, the German Center for Neurodegenerative Diseases (DZNE) and Charité-Universitätsmedizin Berlin have filed a patent application on which J. Kreye., S.M.R., and H.P. are named as inventors of mAb CV07-209. (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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