Key benefits of dexamethasone and antibody treatment in COVID-19 hamster models revealed by single-cell transcriptomics
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:30 |
|---|---|
| Enthalten in: |
Molecular therapy : the journal of the American Society of Gene Therapy - 30(2022), 5 vom: 04. Mai, Seite 1952-1965 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Wyler, Emanuel [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 09.05.2022 Date Revised 05.11.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.ymthe.2022.03.014 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM338698817 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM338698817 | ||
| 003 | DE-627 | ||
| 005 | 20231226001243.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.ymthe.2022.03.014 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1128.xml |
| 035 | |a (DE-627)NLM338698817 | ||
| 035 | |a (NLM)35339689 | ||
| 035 | |a (PII)S1525-0016(22)00173-3 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Wyler, Emanuel |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Key benefits of dexamethasone and antibody treatment in COVID-19 hamster models revealed by single-cell transcriptomics |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 09.05.2022 | ||
| 500 | |a Date Revised 05.11.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a COVID-19 treatment | |
| 650 | 4 | |a SARS-CoV-2 | |
| 650 | 4 | |a antibody | |
| 650 | 4 | |a dexamethasone | |
| 650 | 4 | |a hamster | |
| 650 | 4 | |a monoclonal antibody therapy | |
| 650 | 4 | |a scRNA-seq | |
| 650 | 4 | |a transcriptomics | |
| 650 | 7 | |a Anti-Inflammatory Agents |2 NLM | |
| 650 | 7 | |a Antibodies, Viral |2 NLM | |
| 650 | 7 | |a Antiviral Agents |2 NLM | |
| 650 | 7 | |a Dexamethasone |2 NLM | |
| 650 | 7 | |a 7S5I7G3JQL |2 NLM | |
| 700 | 1 | |a Adler, Julia M |e verfasserin |4 aut | |
| 700 | 1 | |a Eschke, Kathrin |e verfasserin |4 aut | |
| 700 | 1 | |a Teixeira Alves, G |e verfasserin |4 aut | |
| 700 | 1 | |a Peidli, Stefan |e verfasserin |4 aut | |
| 700 | 1 | |a Pott, Fabian |e verfasserin |4 aut | |
| 700 | 1 | |a Kazmierski, Julia |e verfasserin |4 aut | |
| 700 | 1 | |a Michalick, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Kershaw, Olivia |e verfasserin |4 aut | |
| 700 | 1 | |a Bushe, Judith |e verfasserin |4 aut | |
| 700 | 1 | |a Andreotti, Sandro |e verfasserin |4 aut | |
| 700 | 1 | |a Pennitz, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Abdelgawad, Azza |e verfasserin |4 aut | |
| 700 | 1 | |a Postmus, Dylan |e verfasserin |4 aut | |
| 700 | 1 | |a Goffinet, Christine |e verfasserin |4 aut | |
| 700 | 1 | |a Kreye, Jakob |e verfasserin |4 aut | |
| 700 | 1 | |a Reincke, S Momsen |e verfasserin |4 aut | |
| 700 | 1 | |a Prüss, Harald |e verfasserin |4 aut | |
| 700 | 1 | |a Blüthgen, Nils |e verfasserin |4 aut | |
| 700 | 1 | |a Gruber, Achim D |e verfasserin |4 aut | |
| 700 | 1 | |a Kuebler, Wolfgang M |e verfasserin |4 aut | |
| 700 | 1 | |a Witzenrath, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Landthaler, Markus |e verfasserin |4 aut | |
| 700 | 1 | |a Nouailles, Geraldine |e verfasserin |4 aut | |
| 700 | 1 | |a Trimpert, Jakob |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Molecular therapy : the journal of the American Society of Gene Therapy |d 2000 |g 30(2022), 5 vom: 04. Mai, Seite 1952-1965 |w (DE-627)NLM108239381 |x 1525-0024 |7 nnns |
| 773 | 1 | 8 | |g volume:30 |g year:2022 |g number:5 |g day:04 |g month:05 |g pages:1952-1965 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.ymthe.2022.03.014 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 30 |j 2022 |e 5 |b 04 |c 05 |h 1952-1965 | ||