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Plasmodium falciparum resistance to artemisinin derivatives in southeast Asia threatens malaria control and elimination activities worldwide. To monitor the spread of artemisinin resistance, a molecular marker is urgently needed. Here, using whole-genome sequencing of an artemisinin-resistant parasite line from Africa and clinical parasite isolates from Cambodia, we associate mutations in the PF3D7_1343700 kelch propeller domain ('K13-propeller') with artemisinin resistance in vitro and in vivo. Mutant K13-propeller alleles cluster in Cambodian provinces where resistance is prevalent, and the increasing frequency of a dominant mutant K13-propeller allele correlates with the recent spread of resistance in western Cambodia. Strong correlations between the presence of a mutant allele, in vitro parasite survival rates and in vivo parasite clearance rates indicate that K13-propeller mutations are important determinants of artemisinin resistance. K13-propeller polymorphism constitutes a useful molecular marker for large-scale surveillance efforts to contain artemisinin resistance in the Greater Mekong Subregion and prevent its global spread. [ABSTRACT FROM AUTHOR]

Studying the structure of metapopulations is a new concept in population genetics of infectious diseases that is particularly adapted to the analysis of parasite populations. We considered one application of this theory focusing on Plasmodium falciparum populations. Our study consisted of three main steps: the relevance of the approach, the proposal of a simplified model using metapopulation concepts, and the exploration of the consequences on antimalarial drug resistance. Our main result concerns the metapopulation structure that is appropriate in some real situations. In intertropical rural Africa, parasite populations can be considered to be patchy, comparable to the panmictic situation in which a high transmission rate associated with a high prevalence (generally higher than 50%) implies that no diferenciation occurs between sub populations. In contrast, in Asia and South America, there are great variations in endemicity (with prevalences ranging from 0 to 100%) consistent with a typical metapopulation dynamic structure and a high probability of differentiation between patches. These findings agree with the observed emergence of chloroquine resistance in south-east Asia and South American but not in Africa, and with its rapid spread following its introduction. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Artemisinin is the most widely-used compound against malaria and plays a critical role in the treatment of malaria worldwide. Resistance to artemisinin emerged about a decade ago in Southeast Asia and it is paramount to prevent its spread or emergence in Africa. Artemisinin has a complex mode of action and can cause widespread injury to many components of the parasite. In this review, we outline the different metabolic pathways affected by artemisinin, including the unfolded protein response, protein polyubiquitination, proteasome, phosphatidylinositol-3-kinase, and the eukaryotic translation initiation factor 2α. Based on recently published data, we present a model of how these different pathways interplay and how mutations in K13, the main identified resistance marker, may help parasites survive under artemisinin pressure. Artemisinin is currently the most widely used and effective compound against malaria parasites and it plays a critical role in treatment and ongoing control efforts of malaria worldwide. Unfortunately, emergence of resistance to artemisinin has occurred in Southeast Asia and was shown to be associated with mutations in the K13 gene. Artemisinin kills parasites by increasing oxidative stress in the infected red blood cell, leading to an increased level of unfolded protein. The unfolded protein response of the parasite is associated with a PK4/EIf2a response that can lead to parasite latency. K13 mutations are thought to alter ubiquitination patterns and help parasites to resist the accumulation of polyubiquinated proteins. How these two pathways interplay is not fully understood. Recombinant parasite and single-cell technologies provide powerful avenues to decipher the mode of action of artemisinin and the function of K13. [ABSTRACT FROM AUTHOR]