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Multigenic architecture of piperaquine resistance trait in Plasmodium falciparum

2019; Elsevier BV; Volume: 20; Issue: 1 Linguagem: Inglês

10.1016/s1473-3099(19)30689-9

1474-4457

Miguel Silva, Carla Calçada, Miguel Teixeira, María Isabel Veiga, Pedro Eduardo Ferreira,

Drug-Induced Hepatotoxicity and Protection

William L Hamilton and colleagues1Hamilton WL Amato R van der Pluijm RW et al.Evolution and expansion of multidrug-resistant malaria in southeast Asia: a genomic epidemiology study.Lancet Infect Dis. 2019; 19: 943-951Summary Full Text Full Text PDF PubMed Scopus (145) Google Scholar and Rob W van der Pluijm and colleagues2van der Pluijm RW Imwong M Chau NH et al.Determinants of dihydroartemisinin–piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study.Lancet Infect Dis. 2019; 19: 952-961Summary Full Text Full Text PDF PubMed Scopus (177) Google Scholar described the genomic evolution of Plasmodium falciparum malaria and the spread of resistance in this species to dihydroartemisinin–piperaquine in southeast Asia. Resistance in the region has been associated with crt polymorphisms,1Hamilton WL Amato R van der Pluijm RW et al.Evolution and expansion of multidrug-resistant malaria in southeast Asia: a genomic epidemiology study.Lancet Infect Dis. 2019; 19: 943-951Summary Full Text Full Text PDF PubMed Scopus (145) Google Scholar, 2van der Pluijm RW Imwong M Chau NH et al.Determinants of dihydroartemisinin–piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study.Lancet Infect Dis. 2019; 19: 952-961Summary Full Text Full Text PDF PubMed Scopus (177) Google Scholar, 3Ross LS Dhingra SK Mok S et al.Emerging southeast Asian PfCRT mutations confer Plasmodium falciparum resistance to the first-line antimalarial piperaquine.Nat Commun. 2018; 93314Crossref PubMed Scopus (123) Google Scholar copy number variations in plasmepsins,1Hamilton WL Amato R van der Pluijm RW et al.Evolution and expansion of multidrug-resistant malaria in southeast Asia: a genomic epidemiology study.Lancet Infect Dis. 2019; 19: 943-951Summary Full Text Full Text PDF PubMed Scopus (145) Google Scholar, 2van der Pluijm RW Imwong M Chau NH et al.Determinants of dihydroartemisinin–piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study.Lancet Infect Dis. 2019; 19: 952-961Summary Full Text Full Text PDF PubMed Scopus (177) Google Scholar, 3Ross LS Dhingra SK Mok S et al.Emerging southeast Asian PfCRT mutations confer Plasmodium falciparum resistance to the first-line antimalarial piperaquine.Nat Commun. 2018; 93314Crossref PubMed Scopus (123) Google Scholar, 4Witkowski B Duru V Khim N et al.A surrogate marker of piperaquine-resistant Plasmodium falciparum malaria: a phenotype–genotype association study.Lancet Infect Dis. 2017; 17: 174-183Summary Full Text Full Text PDF PubMed Scopus (220) Google Scholar, 5Bopp S Magistrado P Wong W et al.Plasmepsin II-III copy number accounts for bimodal piperaquine resistance among Cambodian Plasmodium falciparum.Nat Commun. 2018; 91769Crossref PubMed Scopus (59) Google Scholar and mdr1 genes.4Witkowski B Duru V Khim N et al.A surrogate marker of piperaquine-resistant Plasmodium falciparum malaria: a phenotype–genotype association study.Lancet Infect Dis. 2017; 17: 174-183Summary Full Text Full Text PDF PubMed Scopus (220) Google Scholar, 5Bopp S Magistrado P Wong W et al.Plasmepsin II-III copy number accounts for bimodal piperaquine resistance among Cambodian Plasmodium falciparum.Nat Commun. 2018; 91769Crossref PubMed Scopus (59) Google Scholar Despite compelling evidence regarding the determinant effect of crt polymorphisms on piperaquine resistance,3Ross LS Dhingra SK Mok S et al.Emerging southeast Asian PfCRT mutations confer Plasmodium falciparum resistance to the first-line antimalarial piperaquine.Nat Commun. 2018; 93314Crossref PubMed Scopus (123) Google Scholar the roles of plasmepsin variation and mdr1 genes, which were first identified in a 2017 phenotype–genotype association study,4Witkowski B Duru V Khim N et al.A surrogate marker of piperaquine-resistant Plasmodium falciparum malaria: a phenotype–genotype association study.Lancet Infect Dis. 2017; 17: 174-183Summary Full Text Full Text PDF PubMed Scopus (220) Google Scholar remain unclear. Therefore, we generated P falciparum Dd2 parasite lines with copy number variations in plasmepsin 2 or a hybrid of the plasmepsin 1 and plasmepsin 3 genes (plasmepsin 3–1) on a southeast-Asian genetic background to study the contribution of plasmepsins to piperaquine resistance (appendix p 1). In the course of generating the transgenic lines, we observed a deamplification of mdr1 copy number in both plasmepsin 2 and plasmepsin 3–1 parasites (appendix p 2), which led to increased susceptibility to mefloquine (appendix p 3). This result corroborates observations of piperaquine-resistance selection in southeast Asia1Hamilton WL Amato R van der Pluijm RW et al.Evolution and expansion of multidrug-resistant malaria in southeast Asia: a genomic epidemiology study.Lancet Infect Dis. 2019; 19: 943-951Summary Full Text Full Text PDF PubMed Scopus (145) Google Scholar, 2van der Pluijm RW Imwong M Chau NH et al.Determinants of dihydroartemisinin–piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study.Lancet Infect Dis. 2019; 19: 952-961Summary Full Text Full Text PDF PubMed Scopus (177) Google Scholar and suggests that the reduction of mdr1 copy number occurs as a result of a cellular physiological digestive-vacuole adaptation to withstand plasmepsin gene amplification events rather than a direct process of selection for piperaquine resistance (appendix p 3). Furthermore, as somewhat expected, we could not detect any significant alteration of these parasite lines at the half maximal inhibitory concentration of piperaquine (appendix p 4). However, given the association of crt mutations with piperaquine resistance,3Ross LS Dhingra SK Mok S et al.Emerging southeast Asian PfCRT mutations confer Plasmodium falciparum resistance to the first-line antimalarial piperaquine.Nat Commun. 2018; 93314Crossref PubMed Scopus (123) Google Scholar we did drug assays using verapamil as an inhibitor of CRT and elacridar as an inhibitor of MDR1. We found that both plasmepsin 2 and plasmepsin 3–1 gene amplifications contributed to piperaquine resistance in the presence of these inhibitors, creating a bimodal effect on piperaquine susceptibility (appendix pp 2, 4), similar to that previously described in Cambodian P falciparum.5Bopp S Magistrado P Wong W et al.Plasmepsin II-III copy number accounts for bimodal piperaquine resistance among Cambodian Plasmodium falciparum.Nat Commun. 2018; 91769Crossref PubMed Scopus (59) Google Scholar This effect was higher with CRT inhibition (area under the curve [AUC] was 74 [95% CI 67–82] for plasmepsin 2 and 42 [37–46] for plasmepsin 3–1) than with MDR1 inhibition (AUC was 47 [95% CI 40–54] for plasmepsin 2 and 29 [24–34] for plasmepsin 3–1; appendix pp 2, 4). In the previous studies, crt mutations associated with piperaquine resistance arose on a genetic background of amplified plasmepsin genes.1Hamilton WL Amato R van der Pluijm RW et al.Evolution and expansion of multidrug-resistant malaria in southeast Asia: a genomic epidemiology study.Lancet Infect Dis. 2019; 19: 943-951Summary Full Text Full Text PDF PubMed Scopus (145) Google Scholar, 2van der Pluijm RW Imwong M Chau NH et al.Determinants of dihydroartemisinin–piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study.Lancet Infect Dis. 2019; 19: 952-961Summary Full Text Full Text PDF PubMed Scopus (177) Google Scholar Together with our data, this finding suggests that although initial selection of plasmepsin and mdr1 copy number variations does not cause a resistant phenotype in itself, it generates a favourable P falciparum genetic background for crt mutations to arise. Altogether, our results recapitulate in vitro a complementary mechanism between plasmepsins, mdr1, and crt involved in piperaquine resistance, supporting the molecular epidemiological data in southeast Asia1Hamilton WL Amato R van der Pluijm RW et al.Evolution and expansion of multidrug-resistant malaria in southeast Asia: a genomic epidemiology study.Lancet Infect Dis. 2019; 19: 943-951Summary Full Text Full Text PDF PubMed Scopus (145) Google Scholar, 2van der Pluijm RW Imwong M Chau NH et al.Determinants of dihydroartemisinin–piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study.Lancet Infect Dis. 2019; 19: 952-961Summary Full Text Full Text PDF PubMed Scopus (177) Google Scholar and furthering understanding of how piperaquine drug resistance evolves. We declare no competing interests. This work was funded by the Northern Portugal Regional Operational Programme, under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (NORTE-01-0145-FEDER-000013, NORTE-01-0145-FEDER-000023, and POCI-01-0145-FEDER-028066); the European Society of Clinical Microbiology and Infectious Diseases Research Grant 2019; the Starting Institute Mérieux Research Grant 2016; and the Fundação para a Ciência e Tecnologia (SFRH/BD/129769/2017 to MS, PD/BD/127826/2016 to CC, DL57/2016(CRP) to MIV, and IF/00143/2015 to PEF). Download .pdf (.64 MB) Help with pdf files Supplementary appendix Evolution and expansion of multidrug-resistant malaria in southeast Asia: a genomic epidemiology studyAfter emerging and circulating for several years within Cambodia, the P falciparum KEL1/PLA1 co-lineage diversified into multiple subgroups and acquired new genetic features, including novel crt mutations. These subgroups have rapidly spread into neighbouring countries, suggesting enhanced fitness. These findings highlight the urgent need for elimination of this increasingly drug-resistant parasite co-lineage, and the importance of genetic surveillance in accelerating malaria elimination efforts. Full-Text PDF Open AccessDeterminants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic studyDihydroartemisinin-piperaquine is not treating malaria effectively across the eastern Greater Mekong subregion. A highly drug-resistant P falciparum co-lineage is evolving, acquiring new resistance mechanisms, and spreading. Accelerated elimination of P falciparum malaria in this region is needed urgently, to prevent further spread and avoid a potential global health emergency. Full-Text PDF Open Access