Plasmodium falciparum reticulocyte-binding homologues are targets of human inhibitory antibodies and play a role in immune evasion
IntroductionAntibodies targeting the blood-stage of Plasmodium falciparum play a critical role in naturally acquired immunity to malaria by limiting blood-stage parasitemia. One mode of action of antibodies is the direct inhibition of merozoite invasion of erythrocytes through targeting invasion lig...
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Frontiers Media S.A.
2025-03-01
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| author | Linda Reiling Linda Reiling Linda Reiling Kristina E. M. Persson Kristina E. M. Persson Fiona J. McCallum Nimmo Gicheru Samson M. Kinyanjui Chetan E. Chitnis Freya J. I. Fowkes Freya J. I. Fowkes Freya J. I. Fowkes Kevin Marsh Kevin Marsh James G. Beeson James G. Beeson James G. Beeson James G. Beeson |
| author_facet | Linda Reiling Linda Reiling Linda Reiling Kristina E. M. Persson Kristina E. M. Persson Fiona J. McCallum Nimmo Gicheru Samson M. Kinyanjui Chetan E. Chitnis Freya J. I. Fowkes Freya J. I. Fowkes Freya J. I. Fowkes Kevin Marsh Kevin Marsh James G. Beeson James G. Beeson James G. Beeson James G. Beeson |
| author_sort | Linda Reiling |
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| description | IntroductionAntibodies targeting the blood-stage of Plasmodium falciparum play a critical role in naturally acquired immunity to malaria by limiting blood-stage parasitemia. One mode of action of antibodies is the direct inhibition of merozoite invasion of erythrocytes through targeting invasion ligands. However, evasion of inhibitory antibodies may be mediated in P. falciparum by switching between various ligand-mediated merozoite invasion pathways. Here, we investigated the potential roles of invasion ligands PfRH1, PfRH2a and PfRH2b in immune evasion through phenotypic variation, and their importance as targets of human invasion-inhibitory antibodies.MethodsSerum samples from malaria-exposed children and adults in Kenya were examined for their ability to inhibit P. falciparum invasion, using parasites with disrupted pfrh1, pfrh2a or pfrh2b genes.Results and DiscussionThe loss of PfRH1 and PfRH2b substantially impacted on susceptibility to inhibitory antibodies, suggesting that variation in the use of these ligands contributes to immune evasion. The effect was less prominent with loss of PfRH2a. Differential inhibition of the knockout and parental lines points to PfRH1 and PfRH2b as targets of acquired growth inhibitory antibodies whereas PfRH2a appeared to be a minor target. There was limited relatedness of the inhibitory responses between different isolates or compared to parasites with deletions of erythrocyte-binding antigens. This further suggests that there is a substantial amount of antigenic diversity in invasion pathways to facilitate immune evasion. These findings provide evidence that PfRH1 and PfRH2b are significant targets of inhibitory antibodies and variation in their expression may facilitate immune evasion. Targeting of multiple invasion ligands in vaccine design is likely to be required to achieve potent inhibitory antibodies and protective efficacy against malaria. |
| format | Article |
| id | doaj-art-4d60ba3e19704b238769d67d953e254d |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-4d60ba3e19704b238769d67d953e254d2025-08-20T03:40:28ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-03-011610.3389/fimmu.2025.15324511532451Plasmodium falciparum reticulocyte-binding homologues are targets of human inhibitory antibodies and play a role in immune evasionLinda Reiling0Linda Reiling1Linda Reiling2Kristina E. M. Persson3Kristina E. M. Persson4Fiona J. McCallum5Nimmo Gicheru6Samson M. Kinyanjui7Chetan E. Chitnis8Freya J. I. Fowkes9Freya J. I. Fowkes10Freya J. I. Fowkes11Kevin Marsh12Kevin Marsh13James G. Beeson14James G. Beeson15James G. Beeson16James G. Beeson17Department of Life Sciences, Burnet Institute of Medical Research and Public Health, Melbourne, VIC, AustraliaDepartment of Medicine, University of Melbourne, VIC, AustraliaDepartment of Immunology, Monash University, Melbourne, VIC, AustraliaDepartment of Laboratory Medicine, Lund University, Lund, SwedenClinical Chemistry and Pharmacology, Skåne University Hospital, Lund, SwedenAustralian Defence Force Malaria and Infectious Disease Institute, Enoggera, QLD, AustraliaCentre for Geographic Medicine Research (Coast), Kenya Medical Research Institute - Wellcome Trust Research Programme, Kilifi, KenyaCentre for Geographic Medicine Research (Coast), Kenya Medical Research Institute - Wellcome Trust Research Programme, Kilifi, KenyaDepartment of Parasites and Insect Vectors, Pasteur Institute, Paris, FranceDepartment of Life Sciences, Burnet Institute of Medical Research and Public Health, Melbourne, VIC, AustraliaCentre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia0Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, AustraliaCentre for Geographic Medicine Research (Coast), Kenya Medical Research Institute - Wellcome Trust Research Programme, Kilifi, Kenya1Nuffield Department of Medicine, Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Oxford, United KingdomDepartment of Life Sciences, Burnet Institute of Medical Research and Public Health, Melbourne, VIC, Australia2Department of Microbiology, Monash University, Melbourne, VIC, Australia3School of Translational Medicine, Monash University, Melbourne, VIC, Australia4Department of Infectious Diseases, University of Melbourne, Melbourne, VIC, AustraliaIntroductionAntibodies targeting the blood-stage of Plasmodium falciparum play a critical role in naturally acquired immunity to malaria by limiting blood-stage parasitemia. One mode of action of antibodies is the direct inhibition of merozoite invasion of erythrocytes through targeting invasion ligands. However, evasion of inhibitory antibodies may be mediated in P. falciparum by switching between various ligand-mediated merozoite invasion pathways. Here, we investigated the potential roles of invasion ligands PfRH1, PfRH2a and PfRH2b in immune evasion through phenotypic variation, and their importance as targets of human invasion-inhibitory antibodies.MethodsSerum samples from malaria-exposed children and adults in Kenya were examined for their ability to inhibit P. falciparum invasion, using parasites with disrupted pfrh1, pfrh2a or pfrh2b genes.Results and DiscussionThe loss of PfRH1 and PfRH2b substantially impacted on susceptibility to inhibitory antibodies, suggesting that variation in the use of these ligands contributes to immune evasion. The effect was less prominent with loss of PfRH2a. Differential inhibition of the knockout and parental lines points to PfRH1 and PfRH2b as targets of acquired growth inhibitory antibodies whereas PfRH2a appeared to be a minor target. There was limited relatedness of the inhibitory responses between different isolates or compared to parasites with deletions of erythrocyte-binding antigens. This further suggests that there is a substantial amount of antigenic diversity in invasion pathways to facilitate immune evasion. These findings provide evidence that PfRH1 and PfRH2b are significant targets of inhibitory antibodies and variation in their expression may facilitate immune evasion. Targeting of multiple invasion ligands in vaccine design is likely to be required to achieve potent inhibitory antibodies and protective efficacy against malaria.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1532451/fullP. falciparuminhibitory antibodiesphenotypic variationimmune evasionreticulocyte binding homologuesRH proteins |
| spellingShingle | Linda Reiling Linda Reiling Linda Reiling Kristina E. M. Persson Kristina E. M. Persson Fiona J. McCallum Nimmo Gicheru Samson M. Kinyanjui Chetan E. Chitnis Freya J. I. Fowkes Freya J. I. Fowkes Freya J. I. Fowkes Kevin Marsh Kevin Marsh James G. Beeson James G. Beeson James G. Beeson James G. Beeson Plasmodium falciparum reticulocyte-binding homologues are targets of human inhibitory antibodies and play a role in immune evasion Frontiers in Immunology P. falciparum inhibitory antibodies phenotypic variation immune evasion reticulocyte binding homologues RH proteins |
| title | Plasmodium falciparum reticulocyte-binding homologues are targets of human inhibitory antibodies and play a role in immune evasion |
| title_full | Plasmodium falciparum reticulocyte-binding homologues are targets of human inhibitory antibodies and play a role in immune evasion |
| title_fullStr | Plasmodium falciparum reticulocyte-binding homologues are targets of human inhibitory antibodies and play a role in immune evasion |
| title_full_unstemmed | Plasmodium falciparum reticulocyte-binding homologues are targets of human inhibitory antibodies and play a role in immune evasion |
| title_short | Plasmodium falciparum reticulocyte-binding homologues are targets of human inhibitory antibodies and play a role in immune evasion |
| title_sort | plasmodium falciparum reticulocyte binding homologues are targets of human inhibitory antibodies and play a role in immune evasion |
| topic | P. falciparum inhibitory antibodies phenotypic variation immune evasion reticulocyte binding homologues RH proteins |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1532451/full |
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