Key benefits of dexamethasone and antibody treatment in COVID-19 hamster models revealed by single cell transcriptomics
Authors
- E. Wyler
- J.M. Adler
- K. Eschke
- G. Teixeira Alves
- S. Peidli
- F. Pott
- J. Kazmierski
- L. Michalick
- O. Kershaw
- J. Bushe
- S. Andreotti
- P. Pennitz
- A. Abdelgawad
- D. Postmus
- C. Goffinet
- J. Kreye
- S.M. Reincke
- H. Prüss
- N. Blüthgen
- A.D. Gruber
- W.M. Kuebler
- M. Witzenrath
- M. Landthaler
- G. Nouailles
- J. Trimpert
Journal
- Molecular Therapy
Citation
- Mol Ther 30 (5): 1952-1965
Abstract
For 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-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 similar 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.