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 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 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.
Highlights
Despite recent advances in chemotherapeutics, diagnostics and vector control measures, malaria continues to exert a significant impact on human health (Hanboonkunupakarn and White, 2020)
We calculated the fitness cost, which represents the percent reduction in growth rate per 48 hr generation of a test line compared to its wild-type isogenic comparator. These costs ranged from
Mutant K13-mediated ART resistance has substantially compromised the efficacy of antimalarial treatments across SE Asia, and the relatively high prevalence of the R561H variant that has recently been associated with delayed clearance in Rwanda highlights the risk of ART resistance emerging and spreading in sub-Saharan Africa (Uwimana et al, 2020; Bergmann et al, 2021; Uwimana et al, 2021)
Summary
Despite recent advances in chemotherapeutics, diagnostics and vector control measures, malaria continues to exert a significant impact on human health (Hanboonkunupakarn and White, 2020). In the absence of an effective licensed malaria vaccine, control and elimination strategies are critically reliant on the continued clinical efficacy of first-line artemisinin-based combination therapies (ACTs) (White et al, 2014) These ACTs pair fast-acting artemisinin (ART) derivatives with partner drugs such as lumefantrine, amodiaquine, mefloquine, or piperaquine (PPQ). Other studies have documented the emergence of nearly 200 other K13 mutations, both in SE Asia and in other malaria-endemic regions, including the Guiana Shield and the western Pacific (MalariaGEN Plasmodium falciparum Community Project, 2016; Menard et al, 2016; Das et al, 2019; WWARN K13 Genotype-Phenotype Study Group, 2019; Mathieu et al, 2020; Miotto et al, 2020). Our data highlight the threat of the R561H mutation emerging in Rwanda, which confers elevated RSA survival and a minimal fitness cost in African 3D7 parasites
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