Early Reduction of SARS-CoV-2 Replication in Bronchial Epithelium by Kinin B 2 Receptor Antagonism

  1. Constanze A. Jakwerth
  2. Martin Feuerherd
  3. Ferdinand M. Guerth
  4. Madlen Oelsner
  5. Linda Schellhammer
  6. Johanna Giglberger
  7. Lisa Pechtold
  8. Claudia Jerin
  9. Luisa Kugler
  10. Carolin Mogler
  11. Bernhard Haller
  12. Anna Erb
  13. Barbara Wollenberg
  14. Christoph D. Spinner
  15. Thorsten Buch
  16. Ulrike Protzer
  17. Carsten B. Schmidt-Weber
  18. Ulrich M. Zissler
  19. Adam M. Chaker
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Abstract

Background

SARS-CoV2 has evolved to enter the host via the ACE2 receptor which is part of the Kinin-kallirein pathway. This complex pathway is only poorly understood in context of immune regulation but critical to control infection. This study examines SARS-CoV2 infection and epithelial mechanisms of the kinin-kallikrein system at the kinin B 2 receptor level in SARS-CoV-2 infection that is of direct translational relevance.

Methods

From acute SARS-CoV-2-positive patients and -negative controls, transcriptomes of nasal brushings were analyzed. Primary airway epithelial cells (NHBEs) were infected with SARS-CoV-2 and treated with the approved B 2 R antagonist icatibant. SARS-CoV-2 RNA RT-qPCR, cytotoxicity assays, plaque assays and transcriptome analyses were performed. The treatment effect was further studied in a murine airway inflammation model in vivo .

Results

Here, we report a broad and strong upregulation of kallikreins and the kinin B 2 receptor (B 2 R) in the nasal mucosa of acutely symptomatic SARS-CoV-2-positive patients. A B 2 R antagonist impeded SARS-CoV-2 replication and spread in NHBEs, as determined in plaque assays on Vero E6 cells. B 2 R antagonism reduced the expression of SARS-CoV-2 entry receptor ACE2 in vitro and in a murine airway inflammation model in vivo . In addition, it suppressed gene expression broadly, particularly genes involved in G-protein-coupled-receptor signaling and ion transport.

Conclusions

In summary, this study provides evidence that treatment with B 2 R antagonists protects airway epithelial cells from SARS-CoV-2 by inhibiting its replication and spread, through the reduction of ACE2 levels and the interference with several cellular signaling processes. Future clinical studies need to shed light on the airway protection potential of approved B 2 R antagonists, like icatibant, in the treatment of early-stage COVID-19.

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