P. falciparum K13 mutations present varying degrees of artemisinin resistance and reduced fitness in African parasites

Abstract

The emergence of artemisinin (ART) resistance in Plasmodium falciparum parasites, driven by K13 mutations, has led to widespread antimalarial treatment failure in Southeast Asia. In Africa, our genotyping of 3,299 isolates confirms the emergence of the K13 R561H variant in Rwanda and reveals the continuing dominance of wild-type K13 across 11 countries. We show that this mutation, along with M579I and C580Y, confers varying degrees of in vitro ART resistance in African parasites. C580Y and M579I cause substantial fitness costs, which may counter-select against their dissemination in high-transmission settings. We also define the impact of multiple K13 mutations on ART resistance and fitness in multiple Southeast Asian strains. ART susceptibility is unaltered upon editing point mutations in ferrodoxin or mdr2, earlier resistance markers. These data point to the lack of an evident biological barrier to mutant K13 mediating ART resistance in Africa, while identifying their detrimental impact on parasite growth.

Screening and characterization of antimalarial resistance related genetic structural variations in P. falciparum

“…Among factors known to contribute to proliferation assay outcome as discussed previously in PMII discussion section, perhaps the lack of change in IDC duration explains the lack of decreasing effect observed on K13mt proliferation rate. In respective to studies of transgenic in vitro model of pfk13 allele variants, the mutation in pfk13 has shown to incur fitness cost measured by growth rate and competition assays[76,249,250] whereby the genetic background of parental strain speculated as a contributing factor to the outcome[250,251]. However, a study of transgenic pfk13 C580Y on P. falciparum 3D7 background shown a marginal reduction in parasite fitness[74].…”