TY - JOUR
T1 - Early reduction of SARS-CoV-2-replication in bronchial epithelium by kinin B2 receptor antagonism
AU - Jakwerth, Constanze A.
AU - Feuerherd, Martin
AU - Guerth, Ferdinand M.
AU - Oelsner, Madlen
AU - Schellhammer, Linda
AU - Giglberger, Johanna
AU - Pechtold, Lisa
AU - Jerin, Claudia
AU - Kugler, Luisa
AU - Mogler, Carolin
AU - Haller, Bernhard
AU - Erb, Anna
AU - Wollenberg, Barbara
AU - Spinner, Christoph D.
AU - Buch, Thorsten
AU - Protzer, Ulrike
AU - Schmidt-Weber, Carsten B.
AU - Zissler, Ulrich M.
AU - Chaker, Adam M.
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/4
Y1 - 2022/4
N2 - 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 B2 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 B2R-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 B2 receptor (B2R) in the nasal mucosa of acutely symptomatic SARS-CoV-2-positive study participants. A B2R-antagonist impeded SARS-CoV-2 replication and spread in NHBEs, as determined in plaque assays on Vero-E6 cells. B2R-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 B2R-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 B2R-antagonists, like icatibant, in the treatment of early-stage COVID-19. Graphical Abstract: [Figure not available: see fulltext.] Key messages: Induction of kinin B2 receptor in the nose of SARS-CoV-2-positive patients.Treatment with B2R-antagonist protects airway epithelial cells from SARS-CoV-2.B2R-antagonist reduces ACE2 levels in vivo and ex vivo.Protection by B2R-antagonist is mediated by inhibiting viral replication and spread.
AB - 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 B2 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 B2R-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 B2 receptor (B2R) in the nasal mucosa of acutely symptomatic SARS-CoV-2-positive study participants. A B2R-antagonist impeded SARS-CoV-2 replication and spread in NHBEs, as determined in plaque assays on Vero-E6 cells. B2R-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 B2R-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 B2R-antagonists, like icatibant, in the treatment of early-stage COVID-19. Graphical Abstract: [Figure not available: see fulltext.] Key messages: Induction of kinin B2 receptor in the nose of SARS-CoV-2-positive patients.Treatment with B2R-antagonist protects airway epithelial cells from SARS-CoV-2.B2R-antagonist reduces ACE2 levels in vivo and ex vivo.Protection by B2R-antagonist is mediated by inhibiting viral replication and spread.
KW - ACE2
KW - BR-antagonist
KW - COVID-19
KW - Kinin
KW - Kinin-kallikrein-system
KW - SARS-CoV-2
UR - http://www.scopus.com/inward/record.url?scp=85125755115&partnerID=8YFLogxK
U2 - 10.1007/s00109-022-02182-7
DO - 10.1007/s00109-022-02182-7
M3 - Article
C2 - 35247068
AN - SCOPUS:85125755115
SN - 0946-2716
VL - 100
SP - 613
EP - 627
JO - Journal of Molecular Medicine
JF - Journal of Molecular Medicine
IS - 4
ER -