Abstract
BackgroundMutations in the Plasmodium falciparum k13 gene are associated with artemisinin (ART) resistance. However, it is unclear whether the F446I mutation, the most prevalent allele at the China–Myanmar border and north of Myanmar, is associated with ART resistance. Therefore, the aim of this study was to investigate the role of this mutation in ART resistance by generating transgenic parasites expressing the F446I mutant allele.MethodsThe transgenic parasites carrying the F446I or C580Y mutation in both 3D7 and FCC1/HN isolates were generated by single crossing-over recombination and verified using PCR and gene sequencing. The ring-stage survival assay of 0–3 h (RSA0–3 h) was used to evaluate ART susceptibility of the transgenic parasites in vitro.ResultsFour transgenic parasite lines named 3D7F446I mut, 3D7C580Y mut, FCC1/HNF446I mut and FCC1/HNC580Y mut were successfully generated. These parasite lines showed no changes in the expression level of k13 when compared with their parent parasite isolates. However, introduction of the F446I mutation in k13 of the 3D7 and FCC1/HN isolates led to elevated ring survival rates detected using RSA0–3 h when subjected to both 700 and 20 nM concentrations of dihydroartemisinin. The survival rates were similar to those detected in the parasite lines with the C580Y mutation.ConclusionsInsertion of the F446I mutation in k13 led to increased ring survival, suggesting that this mutation may be associated with ART resistance and could be used as a molecular marker for monitoring ART-resistant parasites. The results also highlights the importance of surveillance of F446I mutants for containing the resistant parasite.
Highlights
Introduction ofF446I mutation in the K13 propeller gene leads to increased ring survival rates in Plasmodium falciparum isolatesJing Wang1, Yufu Huang1, Yuemeng Zhao2, Run Ye1, Dongmei Zhang1* and Weiqing Pan1,2* Abstract
In 2008, ART resistance was reported in Plasmodium falciparum parasites in western Cambodia; a delay in clearance time was observed in infected patients who had received the standard 3-day treatment [4, 5]
Tools available for the detection and surveillance of ART-resistant malaria parasites include measurement of in vivo parasite clearance rates and ring-stage survival assay of 0–3 h (RSA0–3 h) that is well correlated with in vivo parasite clearance rates [8]
Summary
Introduction ofF446I mutation in the K13 propeller gene leads to increased ring survival rates in Plasmodium falciparum isolatesJing Wang, Yufu Huang, Yuemeng Zhao, Run Ye1, Dongmei Zhang1* and Weiqing Pan1,2* Abstract. F446I mutation in the K13 propeller gene leads to increased ring survival rates in Plasmodium falciparum isolates. Mutations in the Plasmodium falciparum k13 gene are associated with artemisinin (ART) resistance. It is unclear whether the F446I mutation, the most prevalent allele at the China–Myanmar border and north of Myanmar, is associated with ART resistance. The aim of this study was to investigate the role of this mutation in ART resistance by generating transgenic parasites expressing the F446I mutant allele. In 2008, ART resistance was reported in Plasmodium falciparum parasites in western Cambodia; a delay in clearance time was observed in infected patients who had received the standard 3-day treatment [4, 5].
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