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...
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eLife Sciences Publications Ltd
2025-01-01
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| Online Access: | https://elifesciences.org/articles/97865 |
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| author | Axelle Amen Randy Yoo Amanda Fabra-García Judith Bolscher William JR Stone Isabelle Bally Sebastián Dergan-Dylon Iga Kucharska Roos M de Jong Marloes de Bruijni Teun Bousema C Richter King Randall S MacGill Robert W Sauerwein Jean-Philippe Julien Pascal Poignard Matthijs M Jore |
| author_facet | Axelle Amen Randy Yoo Amanda Fabra-García Judith Bolscher William JR Stone Isabelle Bally Sebastián Dergan-Dylon Iga Kucharska Roos M de Jong Marloes de Bruijni Teun Bousema C Richter King Randall S MacGill Robert W Sauerwein Jean-Philippe Julien Pascal Poignard Matthijs M Jore |
| author_sort | Axelle Amen |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-55e2a63efbd2420980a4c85f3a080aa1 |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-55e2a63efbd2420980a4c85f3a080aa12025-01-16T13:39:16ZengeLife Sciences Publications LtdeLife2050-084X2025-01-011310.7554/eLife.97865Target-agnostic identification of human antibodies to Plasmodium falciparum sexual forms reveals cross-stage recognition of glutamate-rich repeatsAxelle Amen0https://orcid.org/0000-0002-0449-4445Randy Yoo1https://orcid.org/0000-0002-6952-9039Amanda Fabra-García2https://orcid.org/0000-0001-6663-213XJudith Bolscher3https://orcid.org/0000-0002-1898-6096William JR Stone4https://orcid.org/0000-0002-6647-0166Isabelle Bally5Sebastián Dergan-Dylon6Iga Kucharska7Roos M de Jong8Marloes de Bruijni9Teun Bousema10https://orcid.org/0000-0003-2666-094XC Richter King11Randall S MacGill12https://orcid.org/0000-0002-4566-1481Robert W Sauerwein13Jean-Philippe Julien14https://orcid.org/0000-0001-7602-3995Pascal Poignard15https://orcid.org/0000-0002-0021-7192Matthijs M Jore16https://orcid.org/0000-0002-0686-370XCNRS, Université Grenoble Alpes, CEA, UMR5075, Institut de Biologie Structurale, Grenoble, France; CHU Grenoble Alpes, Grenoble, FranceProgram in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, Canada; Department of Biochemistry, University of Toronto, Toronto, CanadaDepartment of Medical Microbiology, Radboud University Medical Center, Nijmegen, NetherlandsTropIQ Health Sciences, Nijmegen, NetherlandsDepartment of Immunology and Infection, London School of Hygiene and Tropical Medicine, London, United KingdomCNRS, Université Grenoble Alpes, CEA, UMR5075, Institut de Biologie Structurale, Grenoble, FranceCNRS, Université Grenoble Alpes, CEA, UMR5075, Institut de Biologie Structurale, Grenoble, FranceProgram in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, CanadaDepartment of Medical Microbiology, Radboud University Medical Center, Nijmegen, NetherlandsTropIQ Health Sciences, Nijmegen, NetherlandsDepartment of Medical Microbiology, Radboud University Medical Center, Nijmegen, NetherlandsCenter for Vaccine Innovation and Access, PATH, Washington D.C., United StatesCenter for Vaccine Innovation and Access, PATH, Washington D.C., United StatesTropIQ Health Sciences, Nijmegen, NetherlandsProgram in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, Canada; Department of Biochemistry, University of Toronto, Toronto, Canada; Department of Immunology, University of Toronto, Toronto, CanadaCNRS, Université Grenoble Alpes, CEA, UMR5075, Institut de Biologie Structurale, Grenoble, France; CHU Grenoble Alpes, Grenoble, FranceDepartment of Medical Microbiology, Radboud University Medical Center, Nijmegen, NetherlandsCirculating 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.https://elifesciences.org/articles/97865gametocytesgametesmonoclonal antibodyrepeat motifhomotypic interactionstransmission-blocking |
| spellingShingle | Axelle Amen Randy Yoo Amanda Fabra-García Judith Bolscher William JR Stone Isabelle Bally Sebastián Dergan-Dylon Iga Kucharska Roos M de Jong Marloes de Bruijni Teun Bousema C Richter King Randall S MacGill Robert W Sauerwein Jean-Philippe Julien Pascal Poignard Matthijs M Jore Target-agnostic identification of human antibodies to Plasmodium falciparum sexual forms reveals cross-stage recognition of glutamate-rich repeats eLife gametocytes gametes monoclonal antibody repeat motif homotypic interactions transmission-blocking |
| title | Target-agnostic identification of human antibodies to Plasmodium falciparum sexual forms reveals cross-stage recognition of glutamate-rich repeats |
| title_full | Target-agnostic identification of human antibodies to Plasmodium falciparum sexual forms reveals cross-stage recognition of glutamate-rich repeats |
| title_fullStr | Target-agnostic identification of human antibodies to Plasmodium falciparum sexual forms reveals cross-stage recognition of glutamate-rich repeats |
| title_full_unstemmed | Target-agnostic identification of human antibodies to Plasmodium falciparum sexual forms reveals cross-stage recognition of glutamate-rich repeats |
| title_short | Target-agnostic identification of human antibodies to Plasmodium falciparum sexual forms reveals cross-stage recognition of glutamate-rich repeats |
| title_sort | target agnostic identification of human antibodies to plasmodium falciparum sexual forms reveals cross stage recognition of glutamate rich repeats |
| topic | gametocytes gametes monoclonal antibody repeat motif homotypic interactions transmission-blocking |
| url | https://elifesciences.org/articles/97865 |
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