Early reduction of SARS-CoV-2-replication in bronchial epithelium by kinin B2 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

SARS-CoV-2 has evolved to enter the host via the ACE2 receptor which is part of the kinin-kallikrein pathway. This complex pathway is only poorly understood in context of immune regulation but critical to control infection. This study examines SARS-CoV-2-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. From acute SARS-CoV-2-positive study participants and -negative controls, transcriptomes of nasal curettages 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. 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 study participants. 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, G protein–coupled receptor signaling, and ion transport in vitro and in a murine airway inflammation in vivo model. 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.

Graphical Abstract

Key messages

  • Induction of kinin B 2 receptor in the nose of SARS-CoV-2-positive patients.

  • Treatment with B 2 R-antagonist protects airway epithelial cells from SARS-CoV-2.

  • B 2 R-antagonist reduces ACE2 levels in vivo and ex vivo.

  • Protection by B 2 R-antagonist is mediated by inhibiting viral replication and spread.

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  1. Version published to 10.1007/s00109-022-02182-7
  2. ScreenIT

    SciScore for 10.1101/2021.08.13.21262037: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsIRB: 2.1 Patients and nasal brushings: The nasal brushings were performed as a part of a larger health professional observational cohort study, which was approved by the ethics commission of the Technical University of Munich (AZ 175/20s).
    Consent: All patients gave written, informed consent prior to participation (see Table 1).
    Euthanasia Agents: The experiment was terminated by CO2 asphyxiation 6 hours or 24 hours after the injection of icatibant.
    Field Sample Permit: All procedures described in this study had previously been approved by the Cantonal Veterinarian’s Office of Zurich, Switzerland (License ZH096/20), and every effort was made to minimize the number of animals used and their suffering.
    Sex as a biological variableBoth sexes were included for each strain and means of each mouse type (strain / sex) are depicted as single values in Fig.2A: circle: female; triangle: male. Black: C57BL/6, mid grey: C3H HeN, light grey: BALB/c strain.
    RandomizationExperiments were performed and analyzed in a randomized and blinded fashion.
    BlindingExperiments were performed and analyzed in a randomized and blinded fashion.
    Power Analysisnot detected.

    Table 2: Resources

    Experimental Models: Organisms/Strains
    SentencesResources
    Mice enrolled in the experiment were 6-8 weeks old, from either C57BL/6J, BALB/c or C3H HeN strains.
    C57BL/6J
    suggested: None
    BALB/c
    suggested: None
    Both sexes were included for each strain and means of each mouse type (strain / sex) are depicted as single values in Fig.2A: circle: female; triangle: male. Black: C57BL/6, mid grey: C3H HeN, light grey: BALB/c strain.
    C57BL/6
    suggested: None

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

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  3. Version published to 10.1101/2021.08.13.21262037v1 on medRxiv