An all-in-one pipeline for the in vitro discovery and in vivo testing of Plasmodium falciparum malaria transmission blocking drugs
Abstract Elimination of malaria will require new drugs with potent activity against Plasmodium falciparum mature stage V gametocytes, the only stages infective to the mosquito vector. The identification and comprehensive validation of molecules active against these quiescent stages is difficult due...
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62014-3 |
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| author | Nicolas M. B. Brancucci Christin Gumpp Geert-Jan van Gemert Xiao Yu Armin Passecker Flore Nardella Basil T. Thommen Marc Chambon Gerardo Turcatti Ludovic Halby Benjamin Blasco Maëlle Duffey Paola B. Arimondo Teun Bousema Artur Scherf Didier Leroy Taco W. A. Kooij Matthias Rottmann Till S. Voss |
| author_facet | Nicolas M. B. Brancucci Christin Gumpp Geert-Jan van Gemert Xiao Yu Armin Passecker Flore Nardella Basil T. Thommen Marc Chambon Gerardo Turcatti Ludovic Halby Benjamin Blasco Maëlle Duffey Paola B. Arimondo Teun Bousema Artur Scherf Didier Leroy Taco W. A. Kooij Matthias Rottmann Till S. Voss |
| author_sort | Nicolas M. B. Brancucci |
| collection | DOAJ |
| description | Abstract Elimination of malaria will require new drugs with potent activity against Plasmodium falciparum mature stage V gametocytes, the only stages infective to the mosquito vector. The identification and comprehensive validation of molecules active against these quiescent stages is difficult due to the specific biology of gametocytes, challenges linked to their cultivation in vitro and the lack of animal models suitable for evaluating the transmission-blocking potential of drug candidates in vivo. Here, we present a transmission-blocking drug discovery and development platform that builds on transgenic NF54/iGP1_RE9Hulg8 parasites engineered to conditionally produce large numbers of stage V gametocytes expressing a red-shifted firefly luciferase viability reporter. Besides developing a robust in vitro screening assay for the reliable identification of stage V gametocytocidal compounds, we also establish a preclinical in vivo malaria transmission model based on infecting female humanized NODscidIL2Rγnull mice with pure NF54/iGP1_RE9Hulg8 stage V gametocytes. Using whole animal bioluminescence imaging, we assess the in vivo gametocyte killing and clearance kinetics of antimalarial reference drugs and clinical drug candidates and identify markedly different pharmacodynamic response profiles. Finally, we combine this mouse model with mosquito feeding assays and thus firmly establish a valuable tool for the systematic in vivo evaluation of transmission-blocking drug efficacy. |
| format | Article |
| id | doaj-art-aaf39398d99347d3b187f2b18324ba3d |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-aaf39398d99347d3b187f2b18324ba3d2025-08-20T03:46:28ZengNature PortfolioNature Communications2041-17232025-07-0116112110.1038/s41467-025-62014-3An all-in-one pipeline for the in vitro discovery and in vivo testing of Plasmodium falciparum malaria transmission blocking drugsNicolas M. B. Brancucci0Christin Gumpp1Geert-Jan van Gemert2Xiao Yu3Armin Passecker4Flore Nardella5Basil T. Thommen6Marc Chambon7Gerardo Turcatti8Ludovic Halby9Benjamin Blasco10Maëlle Duffey11Paola B. Arimondo12Teun Bousema13Artur Scherf14Didier Leroy15Taco W. A. Kooij16Matthias Rottmann17Till S. Voss18Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health InstituteDepartment of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health InstituteDepartment of Medical Microbiology, Radboudumc Center for Infectious Diseases, Radboud University Medical CenterDepartment of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health InstituteDepartment of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health InstituteBiology of Host-Parasite Interactions, Department of Parasites and Insect Vectors, Institut Pasteur, CNRS EMR9195, INSERM U1201, Université de Paris-CitéDepartment of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health InstituteBiomolecular Screening Facility, École Polytechnique Fédérale de Lausanne (EPFL)Biomolecular Screening Facility, École Polytechnique Fédérale de Lausanne (EPFL)Epigenetic Chemical Biology, Department of Structural Biology and Chemistry, Institut Pasteur, CNRS UMR3523 Chem4Life, Université de Paris-CitéMedicines for Malaria VentureMedicines for Malaria VentureEpigenetic Chemical Biology, Department of Structural Biology and Chemistry, Institut Pasteur, CNRS UMR3523 Chem4Life, Université de Paris-CitéDepartment of Medical Microbiology, Radboudumc Center for Infectious Diseases, Radboud University Medical CenterBiology of Host-Parasite Interactions, Department of Parasites and Insect Vectors, Institut Pasteur, CNRS EMR9195, INSERM U1201, Université de Paris-CitéMedicines for Malaria VentureDepartment of Medical Microbiology, Radboudumc Center for Infectious Diseases, Radboud University Medical CenterDepartment of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health InstituteDepartment of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health InstituteAbstract Elimination of malaria will require new drugs with potent activity against Plasmodium falciparum mature stage V gametocytes, the only stages infective to the mosquito vector. The identification and comprehensive validation of molecules active against these quiescent stages is difficult due to the specific biology of gametocytes, challenges linked to their cultivation in vitro and the lack of animal models suitable for evaluating the transmission-blocking potential of drug candidates in vivo. Here, we present a transmission-blocking drug discovery and development platform that builds on transgenic NF54/iGP1_RE9Hulg8 parasites engineered to conditionally produce large numbers of stage V gametocytes expressing a red-shifted firefly luciferase viability reporter. Besides developing a robust in vitro screening assay for the reliable identification of stage V gametocytocidal compounds, we also establish a preclinical in vivo malaria transmission model based on infecting female humanized NODscidIL2Rγnull mice with pure NF54/iGP1_RE9Hulg8 stage V gametocytes. Using whole animal bioluminescence imaging, we assess the in vivo gametocyte killing and clearance kinetics of antimalarial reference drugs and clinical drug candidates and identify markedly different pharmacodynamic response profiles. Finally, we combine this mouse model with mosquito feeding assays and thus firmly establish a valuable tool for the systematic in vivo evaluation of transmission-blocking drug efficacy.https://doi.org/10.1038/s41467-025-62014-3 |
| spellingShingle | Nicolas M. B. Brancucci Christin Gumpp Geert-Jan van Gemert Xiao Yu Armin Passecker Flore Nardella Basil T. Thommen Marc Chambon Gerardo Turcatti Ludovic Halby Benjamin Blasco Maëlle Duffey Paola B. Arimondo Teun Bousema Artur Scherf Didier Leroy Taco W. A. Kooij Matthias Rottmann Till S. Voss An all-in-one pipeline for the in vitro discovery and in vivo testing of Plasmodium falciparum malaria transmission blocking drugs Nature Communications |
| title | An all-in-one pipeline for the in vitro discovery and in vivo testing of Plasmodium falciparum malaria transmission blocking drugs |
| title_full | An all-in-one pipeline for the in vitro discovery and in vivo testing of Plasmodium falciparum malaria transmission blocking drugs |
| title_fullStr | An all-in-one pipeline for the in vitro discovery and in vivo testing of Plasmodium falciparum malaria transmission blocking drugs |
| title_full_unstemmed | An all-in-one pipeline for the in vitro discovery and in vivo testing of Plasmodium falciparum malaria transmission blocking drugs |
| title_short | An all-in-one pipeline for the in vitro discovery and in vivo testing of Plasmodium falciparum malaria transmission blocking drugs |
| title_sort | all in one pipeline for the in vitro discovery and in vivo testing of plasmodium falciparum malaria transmission blocking drugs |
| url | https://doi.org/10.1038/s41467-025-62014-3 |
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