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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.


DOI

doi:10.1016/j.ymthe.2022.03.014