Target-agnostic identification of human antibodies to Plasmodium falciparum sexual forms reveals cross-stage recognition of glutamate-rich repeats

Circulating sexual stages of Plasmodium falciparum (Pf ) can be transmitted from humans to mosquitoes, thereby furthering the spread of malaria in the population. It is well established that antibodies can efficiently block parasite transmission. In search for naturally acquired antibodies targets on sexual stages, we established an efficient method for target-agnostic single B cell activation followed by high-throughput selection of human monoclonal antibodies (mAbs) reactive to sexual stages of Pf in the form of gametes and gametocyte extracts. We isolated mAbs reactive against a range of Pf proteins including well-established targets Pfs48/45 and Pfs230. One mAb, B1E11K, was cross-reactive to various proteins containing glutamate-rich repetitive elements expressed at different stages of the parasite life cycle. A crystal structure of two B1E11K Fab domains in complex with its main antigen, RESA, expressed on asexual blood stages, showed binding of B1E11K to a repeating epitope motif in a head-to-head conformation engaging in affinity-matured homotypic interactions. Thus, this mode of recognition of Pf proteins, previously described only for Pf circumsporozoite protein (PfCSP), extends to other repeats expressed across various stages. The findings augment our understanding of immune-pathogen interactions to repeating elements of the Plasmodium parasite proteome and underscore the potential of the novel mAb identification method used to provide new insights into the natural humoral immune response against Pf .

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Journal
eLife
Published
2024-12-31
DOI
https://doi.org/10.7554/elife.97865.3
Citations
2
Primary Topic
Malaria Research and Control
Type
article
Field-Weighted Citation Impact
1.09

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article

Target-agnostic identification of human antibodies to Plasmodium falciparum sexual forms reveals cross-stage recognition of glutamate-rich repeats

Iga Kucharska, Pascal Poignard, Teun Bousema, Sebastián Dergan‐Dylon et al.
2 citations
eLife
Malaria Research and Control
1.09
article

Target-agnostic identification of human antibodies to Plasmodium falciparum sexual forms reveals cross-stage recognition of glutamate-rich repeats

Iga Kucharska, Pascal Poignard, Teun Bousema, Sebastián Dergan‐Dylon, Marloes de Bruijni, Jean‐Philippe Julien, Randy Yoo, Axelle Amen, Roos M. de Jong, Matthijs M. Jore, Judith M. Bolscher, Isabelle Bally, Robert W. Sauerwein, Amanda Fabra-García, Randall S. MacGill, William J. Stone, C. Richter King
article en
2 citations

Abstract

Circulating sexual stages of Plasmodium falciparum (Pf ) can be transmitted from humans to mosquitoes, thereby furthering the spread of malaria in the population. It is well established that antibodies can efficiently block parasite transmission. In search for naturally acquired antibodies targets on sexual stages, we established an efficient method for target-agnostic single B cell activation followed by high-throughput selection of human monoclonal antibodies (mAbs) reactive to sexual stages of Pf in the form of gametes and gametocyte extracts. We isolated mAbs reactive against a range of Pf proteins including well-established targets Pfs48/45 and Pfs230. One mAb, B1E11K, was cross-reactive to various proteins containing glutamate-rich repetitive elements expressed at different stages of the parasite life cycle. A crystal structure of two B1E11K Fab domains in complex with its main antigen, RESA, expressed on asexual blood stages, showed binding of B1E11K to a repeating epitope motif in a head-to-head conformation engaging in affinity-matured homotypic interactions. Thus, this mode of recognition of Pf proteins, previously described only for Pf circumsporozoite protein (PfCSP), extends to other repeats expressed across various stages. The findings augment our understanding of immune-pathogen interactions to repeating elements of the Plasmodium parasite proteome and underscore the potential of the novel mAb identification method used to provide new insights into the natural humoral immune response against Pf .

eLifeVol. 13
Centre National de la Recherche Scientifique (FR), Radboud University Nijmegen (NL), University of Toronto (CA), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Great Ormond Street Hospital (GB), Centre Hospitalier Universitaire de Grenoble (FR), Hospital for Sick Children (CA), University Medical Center (US), Radboud University Medical Center (NL), CEA Grenoble (FR), London School of Hygiene & Tropical Medicine (GB), SickKids Foundation (CA), Institut de Biologie Structurale (FR), TropIQ Health Sciences (NL), University College London (GB), Université Grenoble Alpes (FR)
U.S. Department of Energy, Bill and Melinda Gates Foundation, Canadian Light Source, Wellcome Trust, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, National Institutes of Health, Office of Science, Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, National Institute of General Medical Sciences, Biological and Environmental Research, Argonne National Laboratory, Brookhaven National Laboratory
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Malaria Research and Control
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