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Early reduction of SARS-CoV-2-replication in bronchial epithelium by kinin B2 receptor antagonism.
Jakwerth, Constanze A; Feuerherd, Martin; Guerth, Ferdinand M; Oelsner, Madlen; Schellhammer, Linda; Giglberger, Johanna; Pechtold, Lisa; Jerin, Claudia; Kugler, Luisa; Mogler, Carolin; Haller, Bernhard; Erb, Anna; Wollenberg, Barbara; Spinner, Christoph D; Buch, Thorsten; Protzer, Ulrike; Schmidt-Weber, Carsten B; Zissler, Ulrich M; Chaker, Adam M.
  • Jakwerth CA; Center of Allergy & Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German, Research Center for Environmental Health, Member of the German Center for Lung Research (DZL), CPC-M, and Member of the Helmholtz I&I Initiative, Biedersteiner Str. 29, 80202, Munich,
  • Feuerherd M; Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, German Center of Infectiology Research (DZIF), Munich partner site, Munich, Germany.
  • Guerth FM; Center of Allergy & Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German, Research Center for Environmental Health, Member of the German Center for Lung Research (DZL), CPC-M, and Member of the Helmholtz I&I Initiative, Biedersteiner Str. 29, 80202, Munich,
  • Oelsner M; Center of Allergy & Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German, Research Center for Environmental Health, Member of the German Center for Lung Research (DZL), CPC-M, and Member of the Helmholtz I&I Initiative, Biedersteiner Str. 29, 80202, Munich,
  • Schellhammer L; Institute of Laboratory Animal Science, University of Zurich, Zurich, Switzerland.
  • Giglberger J; Center of Allergy & Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German, Research Center for Environmental Health, Member of the German Center for Lung Research (DZL), CPC-M, and Member of the Helmholtz I&I Initiative, Biedersteiner Str. 29, 80202, Munich,
  • Pechtold L; Department of Otorhinolaryngology and Head and Neck Surgery, Medical School, Technical University of Munich, Munich, Germany.
  • Jerin C; Department of Otorhinolaryngology and Head and Neck Surgery, Medical School, Technical University of Munich, Munich, Germany.
  • Kugler L; Center of Allergy & Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German, Research Center for Environmental Health, Member of the German Center for Lung Research (DZL), CPC-M, and Member of the Helmholtz I&I Initiative, Biedersteiner Str. 29, 80202, Munich,
  • Mogler C; Department of Otorhinolaryngology and Head and Neck Surgery, Medical School, Technical University of Munich, Munich, Germany.
  • Haller B; Department of Otorhinolaryngology and Head and Neck Surgery, Medical School, Technical University of Munich, Munich, Germany.
  • Erb A; Institute of Pathology, Technical University Munich, Munich, Germany.
  • Wollenberg B; Institute of Medical Informatics, Statistics and Epidemiology, Medical School, Technical University of Munich, Munich, Germany.
  • Spinner CD; Center of Allergy & Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German, Research Center for Environmental Health, Member of the German Center for Lung Research (DZL), CPC-M, and Member of the Helmholtz I&I Initiative, Biedersteiner Str. 29, 80202, Munich,
  • Buch T; Department of Otorhinolaryngology and Head and Neck Surgery, Medical School, Technical University of Munich, Munich, Germany.
  • Protzer U; Department of Internal Medicine II, University Hospital Rechts Der Isar, Medical School, Technical University of Munich, Munich, Germany.
  • Schmidt-Weber CB; Institute of Laboratory Animal Science, University of Zurich, Zurich, Switzerland.
  • Zissler UM; Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, German Center of Infectiology Research (DZIF), Munich partner site, Munich, Germany.
  • Chaker AM; Center of Allergy & Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German, Research Center for Environmental Health, Member of the German Center for Lung Research (DZL), CPC-M, and Member of the Helmholtz I&I Initiative, Biedersteiner Str. 29, 80202, Munich,
J Mol Med (Berl) ; 100(4): 613-627, 2022 04.
Article in English | MEDLINE | ID: covidwho-1729276
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. 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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: J Mol Med (Berl) Journal subject: Molecular Biology / Genetics, Medical Year: 2022 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: J Mol Med (Berl) Journal subject: Molecular Biology / Genetics, Medical Year: 2022 Document Type: Article