Agnostic B cell selection approach identifies antibodies against K. pneumoniae that synergistically drive complement activation

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 sing...

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Published in:	Nature communications Vol. 15; no. 1; pp. 8100 - 17
Main Authors:	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.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 16-09-2024 Nature Publishing Group Nature Portfolio
Subjects:	13/1 13/31 14 45/88 631/250/2501 631/250/251 631/250/255/1318 82/80 Antibiotic resistance Antibodies Antibodies, Bacterial - immunology Antigens B-Lymphocytes - immunology Bacteria Cell activation Complement Complement activation Complement Activation - immunology Functional analysis Genetic analysis Humanities and Social Sciences Humans Immune response Immunoglobulin G Immunoglobulin G - immunology Immunological memory Klebsiella Klebsiella pneumoniae Klebsiella pneumoniae - immunology Lymphocytes B Memory B Cells - immunology Memory cells multidisciplinary Nosocomial infection Nosocomial infections Science Science (multidisciplinary) Surface antigens Target acquisition
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Summary:	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 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. Here, van der Lans et al describe an antigen-agnostic approach to identify antibodies against Klebsiella pneumoniae . Functional analysis of these antibodies indicates that their capacity to activate complement depends on their antigenic target.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-024-52372-9