Agnostic B cell selection approach identifies antibodies against K. pneumoniae that synergistically drive complement activation
van der Lans, Sjors P A; Bardoel, Bart W; Ruyken, Maartje; de Haas, Carla J C; Baijens, Stan; Muts, Remy M; Scheepmaker, Lisette M; Aerts, Piet C; van 't Wout, Marije F L; Preiner, Johannes; Marijnissen, Renoud J; Schuurman, Janine; Beurskens, Frank J; Kerkman, Priscilla F; Rooijakkers, Suzan H M
(2024) Nature Communications, volume 15, issue 1
(Article)
Abstract
Antibody-dependent complement activation plays a key role in the natural human immune response to infections. Currently, the understanding of which antibody-antigen combinations drive a potent complement response on bacteria is limited. Here, we develop an antigen-agnostic approach to stain and single-cell sort human IgG memory B cells recognizing intact bacterial
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cells, keeping surface antigens in their natural context. With this method we successfully identified 29 antibodies against K. pneumoniae, a dominant cause of hospital-acquired infections with increasing antibiotic resistance. Combining genetic tools and functional analyses, we reveal that the capacity of antibodies to activate complement on K. pneumoniae critically depends on their antigenic target. Furthermore, we find that antibody combinations can synergistically activate complement on K. pneumoniae by strengthening each other's binding in an Fc-independent manner. Understanding the molecular basis of effective complement activation by antibody combinations to mimic a polyclonal response could accelerate the development of antibody-based therapies against problematic infections.
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Keywords: Antibodies, Bacterial/immunology, B-Lymphocytes/immunology, Complement Activation/immunology, Humans, Immunoglobulin G/immunology, Klebsiella pneumoniae/immunology, Memory B Cells/immunology, General Chemistry, General Biochemistry,Genetics and Molecular Biology, General Physics and Astronomy, Journal Article
ISSN: 2041-1723
Publisher: Nature Publishing Group
Note: Publisher Copyright: © The Author(s) 2024.
(Peer reviewed)