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
{"title":"恶性疟原虫疟疾传播阻断药物的体外发现和体内试验一条龙管道","authors":"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","doi":"10.1038/s41467-025-62014-3","DOIUrl":null,"url":null,"abstract":"<p>Elimination of malaria will require new drugs with potent activity against <i>Plasmodium falciparum</i> 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_RE9H<sup>ulg8</sup> 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 NODscidIL2Rγ<sup>null</sup> mice with pure NF54/iGP1_RE9H<sup>ulg8</sup> 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.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"22 1","pages":""},"PeriodicalIF":15.7000,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"An all-in-one pipeline for the in vitro discovery and in vivo testing of Plasmodium falciparum malaria transmission blocking drugs\",\"authors\":\"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\",\"doi\":\"10.1038/s41467-025-62014-3\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Elimination of malaria will require new drugs with potent activity against <i>Plasmodium falciparum</i> 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_RE9H<sup>ulg8</sup> 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 NODscidIL2Rγ<sup>null</sup> mice with pure NF54/iGP1_RE9H<sup>ulg8</sup> 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.</p>\",\"PeriodicalId\":19066,\"journal\":{\"name\":\"Nature Communications\",\"volume\":\"22 1\",\"pages\":\"\"},\"PeriodicalIF\":15.7000,\"publicationDate\":\"2025-07-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature Communications\",\"FirstCategoryId\":\"103\",\"ListUrlMain\":\"https://doi.org/10.1038/s41467-025-62014-3\",\"RegionNum\":1,\"RegionCategory\":\"综合性期刊\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MULTIDISCIPLINARY SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Communications","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1038/s41467-025-62014-3","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
An all-in-one pipeline for the in vitro discovery and in vivo testing of Plasmodium falciparum malaria transmission blocking drugs
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.
期刊介绍:
Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.