학술논문

Discovery of highly neutralizing human antibodies targeting Pseudomonas aeruginosa.
Document Type
Academic Journal
Author
Simonis A; Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, 50937 Cologne, Germany. Electronic address: alexander.simonis@uk-koeln.de.; Kreer C; Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.; Albus A; Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.; Rox K; Department of Chemical Biology, Helmholtz Centre for Infection Research (HZI), 38124 Braunschweig, Germany; German Center for Infection Research (DZIF), partner site Hannover-Braunschweig, 38124 Braunschweig, Germany.; Yuan B; Institute of Structural and Systems Biology, University Medical Center Hamburg-Eppendorf (UKE), 22607 Hamburg, Germany; Centre for Structural Systems Biology (CSSB), 22607 Hamburg, Germany; Deutsches Elektronen-Synchrotron Zentrum (DESY), 22607 Hamburg, Germany.; Holzmann D; Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.; Wilms JA; Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.; Zuber S; Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.; Kottege L; Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.; Winter S; Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.; Meyer M; CF Centre, Pediatric Pulmonology and Allergology, University Children's Hospital Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Centre for Rare Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany.; Schmitt K; Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.; Gruell H; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.; Theobald SJ; Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.; Hellmann AM; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; Department of Experimental Pediatric Oncology, University Children's Hospital Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany.; Meyer C; Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.; Ercanoglu MS; Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.; Cramer N; Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, 30625 Hannover, Germany.; Munder A; Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, 30625 Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), German Center for Lung Research, 30625 Hannover, Germany.; Hallek M; Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.; Fätkenheuer G; Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, 50937 Cologne, Germany.; Koch M; Institute for Dental Research and Oral Musculoskeletal Biology, Center for Biochemistry, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.; Seifert H; German Center for Infection Research (DZIF), partner site Bonn-Cologne, 50937 Cologne, Germany; Institute for Medical Microbiology, Immunology and Hygiene, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50935 Cologne, Germany.; Rietschel E; CF Centre, Pediatric Pulmonology and Allergology, University Children's Hospital Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Centre for Rare Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany.; Marlovits TC; Institute of Structural and Systems Biology, University Medical Center Hamburg-Eppendorf (UKE), 22607 Hamburg, Germany; Centre for Structural Systems Biology (CSSB), 22607 Hamburg, Germany; Deutsches Elektronen-Synchrotron Zentrum (DESY), 22607 Hamburg, Germany.; van Koningsbruggen-Rietschel S; CF Centre, Pediatric Pulmonology and Allergology, University Children's Hospital Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Centre for Rare Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany.; Klein F; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, 50937 Cologne, Germany; Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.; Rybniker J; Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; German Center for Infection Research (DZIF), partner site Bonn-Cologne, 50937 Cologne, Germany. Electronic address: jan.rybniker@uk-koeln.de.
Source
Publisher: Cell Press Country of Publication: United States NLM ID: 0413066 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4172 (Electronic) Linking ISSN: 00928674 NLM ISO Abbreviation: Cell Subsets: MEDLINE
Subject
Language
English
Abstract
Drug-resistant Pseudomonas aeruginosa (PA) poses an emerging threat to human health with urgent need for alternative therapeutic approaches. Here, we deciphered the B cell and antibody response to the virulence-associated type III secretion system (T3SS) in a cohort of patients chronically infected with PA. Single-cell analytics revealed a diverse B cell receptor repertoire directed against the T3SS needle-tip protein PcrV, enabling the production of monoclonal antibodies (mAbs) abrogating T3SS-mediated cytotoxicity. Mechanistic studies involving cryoelectron microscopy identified a surface-exposed C-terminal PcrV epitope as the target of highly neutralizing mAbs with broad activity against drug-resistant PA isolates. These anti-PcrV mAbs were as effective as treatment with conventional antibiotics in vivo. Our study reveals that chronically infected patients represent a source of neutralizing antibodies, which can be exploited as therapeutics against PA.
Competing Interests: Declaration of interests A patent application encompassing aspects of this work has been filed by the University of Cologne, listing A.S., C.K., F.K., and J.R. as inventors.
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