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

Emanuel Wyler; Julia M. Adler; Kathrin Eschke; G. Teixeira Alves; Stefan Peidli; Fabian Pott; Julia Kazmierski; Laura Michalick; Olivia Kershaw; Judith Bushe; Sandro Andreotti; Peter Pennitz; Azza Abdelgawad; Dylan Postmus; Christine Goffinet; Jakob Kreye; S. Momsen Reincke; Harald Prüss; Nils Blüthgen; Achim D. Gruber; Wolfgang M. Kuebler; Martin Witzenrath; Markus Landthaler; Geraldine Nouailles; Jakob Trimpert

doi:10.1016/j.ymthe.2022.03.014

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

Emanuel Wyler, Julia M. Adler, Kathrin Eschke, G. Teixeira Alves, Stefan Peidli, Fabian Pott, Julia Kazmierski, Laura Michalick, Olivia Kershaw, Judith Bushe, Sandro Andreotti, Peter Pennitz, Azza Abdelgawad, Dylan Postmus, Christine Goffinet, Jakob Kreye, S. Momsen Reincke, Harald Prüss, Nils Blüthgen, Achim D. GruberWolfgang M. Kuebler, Martin Witzenrath, Markus Landthaler, Geraldine Nouailles, Jakob Trimpert

Research output: Contribution to journal › Article › peer-review

26 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	1952-1965
Number of pages	14
Journal	Molecular Therapy
Volume	30
Issue number	5
DOIs	https://doi.org/10.1016/j.ymthe.2022.03.014
Publication status	Published - 4 May 2022
Externally published	Yes

Keywords

antibody
COVID-19 treatment
dexamethasone
hamster
monoclonal antibody therapy
SARS-CoV-2
scRNA-seq
transcriptomics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Wyler, E., Adler, J. M., Eschke, K., Teixeira Alves, G., Peidli, S., Pott, F., Kazmierski, J., Michalick, L., Kershaw, O., Bushe, J., Andreotti, S., Pennitz, P., Abdelgawad, A., Postmus, D., Goffinet, C., Kreye, J., Reincke, S. M., Prüss, H., Blüthgen, N., ... Trimpert, J. (2022). Key benefits of dexamethasone and antibody treatment in COVID-19 hamster models revealed by single-cell transcriptomics. Molecular Therapy, 30(5), 1952-1965. https://doi.org/10.1016/j.ymthe.2022.03.014

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title = "Key benefits of dexamethasone and antibody treatment in COVID-19 hamster models revealed by single-cell transcriptomics",

abstract = "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.",

keywords = "antibody, COVID-19 treatment, dexamethasone, hamster, monoclonal antibody therapy, SARS-CoV-2, scRNA-seq, transcriptomics",

author = "Emanuel Wyler and Adler, \{Julia M.\} and Kathrin Eschke and \{Teixeira Alves\}, G. and Stefan Peidli and Fabian Pott and Julia Kazmierski and Laura Michalick and Olivia Kershaw and Judith Bushe and Sandro Andreotti and Peter Pennitz and Azza Abdelgawad and Dylan Postmus and Christine Goffinet and Jakob Kreye and Reincke, \{S. Momsen\} and Harald Pr{\"u}ss and Nils Bl{\"u}thgen and Gruber, \{Achim D.\} and Kuebler, \{Wolfgang M.\} and Martin Witzenrath and Markus Landthaler and Geraldine Nouailles and Jakob Trimpert",

year = "2022",

month = may,

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doi = "10.1016/j.ymthe.2022.03.014",

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Wyler, E, Adler, JM, Eschke, K, Teixeira Alves, G, Peidli, S, Pott, F, Kazmierski, J, Michalick, L, Kershaw, O, Bushe, J, Andreotti, S, Pennitz, P, Abdelgawad, A, Postmus, D , Goffinet, C, Kreye, J, Reincke, SM, Prüss, H, Blüthgen, N, Gruber, AD, Kuebler, WM, Witzenrath, M, Landthaler, M, Nouailles, G & Trimpert, J 2022, 'Key benefits of dexamethasone and antibody treatment in COVID-19 hamster models revealed by single-cell transcriptomics', Molecular Therapy, vol. 30, no. 5, pp. 1952-1965. https://doi.org/10.1016/j.ymthe.2022.03.014

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T1 - Key benefits of dexamethasone and antibody treatment in COVID-19 hamster models revealed by single-cell transcriptomics

AU - Wyler, Emanuel

AU - Adler, Julia M.

AU - Eschke, Kathrin

AU - Teixeira Alves, G.

AU - Peidli, Stefan

AU - Pott, Fabian

AU - Kazmierski, Julia

AU - Michalick, Laura

AU - Kershaw, Olivia

AU - Bushe, Judith

AU - Andreotti, Sandro

AU - Pennitz, Peter

AU - Abdelgawad, Azza

AU - Postmus, Dylan

AU - Goffinet, Christine

AU - Kreye, Jakob

AU - Reincke, S. Momsen

AU - Prüss, Harald

AU - Blüthgen, Nils

AU - Gruber, Achim D.

AU - Kuebler, Wolfgang M.

AU - Witzenrath, Martin

AU - Landthaler, Markus

AU - Nouailles, Geraldine

AU - Trimpert, Jakob

PY - 2022/5/4

Y1 - 2022/5/4

N2 - 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.

AB - 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.

KW - antibody

KW - COVID-19 treatment

KW - dexamethasone

KW - hamster

KW - monoclonal antibody therapy

KW - SARS-CoV-2

KW - scRNA-seq

KW - transcriptomics

U2 - 10.1016/j.ymthe.2022.03.014

DO - 10.1016/j.ymthe.2022.03.014

M3 - Article

SN - 1525-0016

VL - 30

SP - 1952

EP - 1965

JO - Molecular Therapy

JF - Molecular Therapy

IS - 5

ER -

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

Abstract

Keywords

UN SDGs

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