| 1. |
- Stokes, B. H., et al.
(författare)
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Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness
- 2021
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Ingår i: eLife. - 2050-084X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- The emergence of mutant K13-mediated artemisinin (ART) resistance in Plasmodium falciparum malaria parasites has led to widespread treatment failures across Southeast Asia. In Africa, K13-propeller genotyping confirms the emergence of the R561 H mutation in Rwanda and highlights the continuing dominance of wild-type K13 elsewhere. Using gene editing, we show that R561 H, along with C580Y and M5791, confer elevated in vitro ART resistance in some African strains, contrasting with minimal changes in ART susceptibility in others. C580Y and M5791 cause substantial fitness costs, which may slow their dissemination in high-transmission settings, in contrast with R561 H that in African 3D7 parasites is fitness neutral. In Cambodia, K13 genotyping highlights the increasing spatio-temporal dominance of C580Y. Editing multiple K13 mutations into a panel of Southeast Asian strains reveals that only the R561 H variant yields ART resistance comparable to C580Y. In Asian Dd2 parasites C580Y shows no fitness cost, in contrast with most other K13 mutations tested, including R561H. Editing of point mutations in ferredoxin or mdr2, earlier associated with resistance, has no impact on ART susceptibility or parasite fitness. These data underline the complex interplay between K13 mutations, parasite survival, growth and genetic background in contributing to the spread of ART resistance.
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| 2. |
- Uwimana, A., et al.
(författare)
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Emergence and clonal expansion of in vitro artemisinin-resistantPlasmodium falciparum kelch13R561H mutant parasites in Rwanda
- 2020
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 26, s. 1602-1608
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Tidskriftsartikel (refereegranskat)abstract
- Artemisinin resistance (delayedP. falciparumclearance following artemisinin-based combination therapy), is widespread across Southeast Asia but to date has not been reported in Africa(1-4). Here we genotyped theP. falciparum K13(Pfkelch13) propeller domain, mutations in which can mediate artemisinin resistance(5,6), in pretreatment samples collected from recent dihydroarteminisin-piperaquine and artemether-lumefantrine efficacy trials in Rwanda(7). While cure rates were >95% in both treatment arms, thePfkelch13R561H mutation was identified in 19 of 257 (7.4%) patients at Masaka. Phylogenetic analysis revealed the expansion of an indigenous R561H lineage. Gene editing confirmed that this mutation can drive artemisinin resistance in vitro. This study provides evidence for the de novo emergence ofPfkelch13-mediated artemisinin resistance in Rwanda, potentially compromising the continued success of antimalarial chemotherapy in Africa. Identification in Rwanda of mutations inPlasmodium falciparumcapable of conferring in vitro resistance to artemisinin, an essential medicine for the treatment of malaria, underscore the crucial need for surveillance in Africa to safeguard efficacy of life-saving therapies.
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| 3. |
- Kümpornsin, Krittikorn, et al.
(författare)
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Generation of a mutator parasite to drive resistome discovery in Plasmodium falciparum
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- In vitro evolution of drug resistance is a powerful approach for identifying antimalarial targets, however, key obstacles to eliciting resistance are the parasite inoculum size and mutation rate. Here we sought to increase parasite genetic diversity to potentiate resistance selections by editing catalytic residues of Plasmodium falciparum DNA polymerase δ. Mutation accumulation assays reveal a ~5–8 fold elevation in the mutation rate, with an increase of 13–28 fold in drug-pressured lines. Upon challenge with the spiroindolone PfATP4-inhibitor KAE609, high-level resistance is obtained more rapidly and at lower inocula than wild-type parasites. Selections also yield mutants with resistance to an “irresistible” compound, MMV665794 that failed to yield resistance with other strains. We validate mutations in a previously uncharacterised gene, PF3D7_1359900, which we term quinoxaline resistance protein (QRP1), as causal for resistance to MMV665794 and a panel of quinoxaline analogues. The increased genetic repertoire available to this “mutator” parasite can be leveraged to drive P. falciparum resistome discovery.
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