A Plasmodium falciparum genetic cross reveals the contributions of pfcrt and plasmepsin II/III to piperaquine drug resistance
Rattachement africain : us, th, gb, kh. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
ABSTRACT Piperaquine (PPQ) is widely used in combination with dihydroartemisinin as a first-line treatment against malaria. Multiple genetic drivers of PPQ resistance have been reported, including mutations in the Plasmodium falciparum chloroquine resistance transporter ( pfcrt ) and increased copies of plasmepsin II/III ( pm2/3 ). We generated a cross between a Cambodia-derived multidrug-resistant KEL1/PLA1 lineage isolate (KH004) and a drug-susceptible Malawian parasite (Mal31). Mal31 harbors a wild-type (3D7-like) pfcrt allele and a single copy of pm2/3 , while KH004 has a chloroquine-resistant (Dd2-like) pfcrt allele with an additional G367C substitution and multiple copies of pm2/3 . We recovered 104 unique recombinant parasites and examined a targeted set of progeny representing all possible combinations of variants at pfcrt and pm2/3 . We performed a detailed analysis of competitive fitness and a range of PPQ susceptibility phenotypes with these progenies, including PPQ survival assay, area under the dose response curve, and a limited point IC 50 . We find that inheritance of the KH004 pfcrt allele is required for reduced PPQ sensitivity, whereas copy number variation in pm2/3 further decreases susceptibility but does not confer resistance in the absence of additional mutations in pfcrt . A deep investigation of genotype-phenotype relationships demonstrates that progeny clones from experimental crosses can be used to understand the relative contributions of pfcrt , pm2/3 , and parasite genetic background to a range of PPQ-related traits. Additionally, we find that the resistance phenotype associated with parasites inheriting the G367C substitution in pfcrt is consistent with previously validated PPQ resistance mutations in this transporter. IMPORTANCE Resistance to piperaquine, used in combination with dihydroartemisinin, has emerged in Cambodia and threatens to spread to other malaria-endemic regions. Understanding the causal mutations of drug resistance and their impact on parasite fitness is critical for surveillance and intervention and can also reveal new avenues to limiting the evolution and spread of drug resistance. An experimental genetic cross is a powerful tool for pinpointing the genetic determinants of key drug resistance and fitness phenotypes and has the distinct advantage of quantifying the effects of naturally evolved genetic variation. Our study was strengthened since the full range of copies of KH004 pm2/3 was inherited among the progeny clones, allowing us to directly test the role of the pm2/3 copy number on resistance-related phenotypes in the context of a unique pfcrt allele. Our multigene model suggests an important role for both loci in the evolution of this multidrug-resistant parasite lineage.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- A <i>Plasmodium falciparum</i> genetic cross reveals the contributions of <i>pfcrt</i> and <i>plasmepsin II/III</i> to piperaquine drug resistance
- Date Crossref
- 17/07/2024
- Éditeur
- American Society for Microbiology
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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University of Notre Dame Department of Biological Sciences pays non établi dans la noticeUniversité ou école supérieure
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Texas Biomedical Research Institute Disease Intervention and Prevention Program pays non établi dans la noticeStructure de recherche
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Infectious Disease Research Institute pays non établi dans la noticeOrganisation à but non lucratif
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Seattle Children's Research Institute Center for Global Infectious Disease Research pays non établi dans la noticeÉtablissement de santé
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Mahidol University pays non établi dans la noticeUniversité ou école supérieure
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University of Oxford Nuffield Department of Medicine Research Building pays non établi dans la noticeUniversité ou école supérieure
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Mahidol Oxford Tropical Medicine Research Unit pays non établi dans la noticeStructure de recherche
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Cambodia National Malaria Center pays non établi dans la noticeOrganisme public
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National Institute of Public Health pays non établi dans la noticeOrganisation à but non lucratif
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University of Washington Department of Pediatrics pays non établi dans la noticeUniversité ou école supérieure
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American Type Culture Collection pays non établi dans la noticeOrganisation à but non lucratif
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Faculty of Tropical Medicine Mahidol-Oxford Tropical Medicine Research Unit pays non établi dans la noticeUniversité ou école supérieure
Department of Biological Sciences — University of Notre Dame, Disease Intervention and Prevention Program — Texas Biomedical Research Institute et Infectious Disease Research Institute, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.