Discovery of highly neutralizing human antibodies targeting Pseudomonas aeruginosa.

Humans Antibodies, Bacterial / pharmacology Cryoelectron Microscopy Immunoglobulins / metabolism Pseudomonas aeruginosa / drug effects Antibodies, Neutralizing Pseudomonas Infections / drug therapy
Pseudomonas aeruginosa anti-virulence therapy antibacterial antibodies antimicrobial resistance monoclonal antibodies patient-derived antibodies type III secretion system

Journal

Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066

Informations de publication

Date de publication:
09 11 2023
Historique:
received: 22 03 2023
revised: 17 07 2023
accepted: 02 10 2023
medline: 13 11 2023
pubmed: 3 11 2023
entrez: 2 11 2023
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.cell.2023.10.002 PMID: 37918395
pubmed: 37918395
pii: S0092-8674(23)01084-X
doi: 10.1016/j.cell.2023.10.002
pii:
doi:

Substances chimiques

Antibodies, Bacterial 0
Immunoglobulins 0
Antibodies, Neutralizing 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

5098-5113.e19

Informations de copyright

Copyright © 2023 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

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.

Auteurs

Alexander 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.

Christoph Kreer (C)

Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.

Alexandra 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.

Katharina 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.

Biao 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.

Dmitriy 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.

Joana A 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.

Sylvia 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.

Lisa Kottege (L)

Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.

Sandra 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.

Meike 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.

Kristin 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.

Henning 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.

Sebastian J 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.

Anna-Maria 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.

Christina 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.

Meryem Seda Ercanoglu (MS)

Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.

Nina Cramer (N)

Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, 30625 Hannover, Germany.

Antje 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.

Michael 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.

Gerd 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.

Manuel 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.

Harald 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.

Ernst 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.

Thomas C 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.

Silke 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.

Florian 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.

Jan 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.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Discovery of highly neutralizing human...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Anticorps › Anticorps antibactériens › Discovery of highly neutralizing human...
questionsmedicales.fr › Techniques d'investigation › Microscopie électronique › Cryomicroscopie électronique › Discovery of highly neutralizing human...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Discovery of highly neutralizing human...
questionsmedicales.fr › Bactéries › Proteobacteria › Gammaproteobacteria › Pseudomonadaceae › Pseudomonas › Pseudomonas aeruginosa › Discovery of highly neutralizing human...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Anticorps › Anticorps neutralisants › Discovery of highly neutralizing human...
questionsmedicales.fr › Infection › Infections bactériennes et mycoses › Infections bactériennes › Infections bactériennes à Gram négatif › Infections à Pseudomonas › Discovery of highly neutralizing human...