Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness

Abstract

The emergence of mutant K13-mediated artemisinin (ART) resistance in Plasmodium falciparum malaria parasites has led to widespread treatment failure across Southeast Asia. In Africa, K13-propeller genotyping confirms the emergence of the R561H mutation in Rwanda and highlights the continuing dominance of wild-type K13 elsewhere. Using gene editing, we show that R561H, along with C580Y and M579I, confer elevated in vitro ART resistance in some African strains, contrasting with minimal changes in ART susceptibility in others. C580Y and M579I cause substantial fitness costs, which may slow their dissemination in high-transmission settings, in contrast with R561H 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 R561H 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 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.

Assessment of Plasmodium falciparum Artemisinin Resistance Independent of kelch13 Polymorphisms and with Escalating Malaria in Bangladesh

“…The P574L mutation, 1 of 10 with WHO-validated resistance, yields an RSA value of 1.5% ( 2 ). F446I, the second most prevalent mutation in Myanmar engineered into lab strain P. falciparum Dd2, shows an RSA value of ∼2.0% ( 33 ). A675V, a recently recognized K13 mutation of AR in Africa, yields an RSA value of 3.5% ( 34 ).…”

Fitness costs of pfhrp2 and pfhrp3 deletions underlying diagnostic evasion in malaria parasites

“…Overall, the fitness costs are ∼0.1 – pfhrp2/3 deleted parasites show 10% lower representation in mixtures every 48h asexual cycle. The costs are of a similar order of magnitude to those observed for many drug resistance loci in the laboratory (17).…”

An improved pharmacometric model for artesunate treatment of falciparum malaria

“…Artemisinin resistance in eld isolates is associated with mutations in the propeller region of the Pfkelch gene on chromosome 13 (K13). This causal association has been con rmed in transfection studies, although the contribution of other genes (often described collectively as the genetic background) is substantial 22 .…”