Abstract
BackgroundArtemisinin-based combination therapies are the first line of treatment for Plasmodium falciparum infections worldwide, but artemisinin resistance has risen rapidly in Southeast Asia over the past decade. Mutations in the kelch13 gene have been implicated in this resistance. We used longitudinal genomic surveillance to detect signals in kelch13 and other loci that contribute to artemisinin or partner drug resistance. We retrospectively sequenced the genomes of 194 P. falciparum isolates from five sites in Northwest Thailand, over the period of a rapid increase in the emergence of artemisinin resistance (2001–2014).ResultsWe evaluate statistical metrics for temporal change in the frequency of individual SNPs, assuming that SNPs associated with resistance increase in frequency over this period. After Kelch13-C580Y, the strongest temporal change is seen at a SNP in phosphatidylinositol 4-kinase, which is involved in a pathway recently implicated in artemisinin resistance. Furthermore, other loci exhibit strong temporal signatures which warrant further investigation for involvement in artemisinin resistance evolution. Through genome-wide association analysis we identify a variant in a kelch domain-containing gene on chromosome 10 that may epistatically modulate artemisinin resistance.ConclusionsThis analysis demonstrates the potential of a longitudinal genomic surveillance approach to detect resistance-associated gene loci to improve our mechanistic understanding of how resistance develops. Evidence for additional genomic regions outside of the kelch13 locus associated with artemisinin-resistant parasites may yield new molecular markers for resistance surveillance, which may be useful in efforts to reduce the emergence or spread of artemisinin resistance in African parasite populations.
Highlights
Artemisinin-based combination therapies are the first line of treatment for Plasmodium falciparum infections worldwide, but artemisinin resistance has risen rapidly in Southeast Asia over the past decade
Dataset filtration We performed an analysis of identity by descent (IBD) among pairwise comparisons of samples within sampling intervals to ascertain changes in the degree of clonality due to recent common ancestry over time, using a hidden Markov model-based approach that makes use of Single nucleotide polymorphism (SNP) calls [31]
The increased IBD among the 2014 samples elevates the linkage disequilibrium (LD) between SNPs, making it difficult to identify signals associated with individual background mutations
Summary
Artemisinin-based combination therapies are the first line of treatment for Plasmodium falciparum infections worldwide, but artemisinin resistance has risen rapidly in Southeast Asia over the past decade. The selective pressure of ACTs on parasite populations is presumably more intense in SE Asia due to lower disease endemicity, commensurately less acquired immunity to disease, and a greater likelihood that infected individuals will become symptomatic and be treated with drugs. This hypothesis is difficult to exclude, but malaria endemicity is highly variable across sub-Saharan Africa and many other regions, and access to ACTs is high in many regions outside of SE Asia [18], making it unlikely that SE Asian drug selection pressure is unique. Mutations conferring resistance to drugs confer deleterious fitness effects that are usually suppressed or mitigated by co-segregating compensatory mutations, a phenomenon well documented in bacteria [19, 20], yeast [21], and P. falciparum [22,23,24]
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