Evidence for linkage of pfmdr1, pfcrt, and pfk13 polymorphisms to lumefantrine and mefloquine susceptibilities in a Plasmodium falciparum cross. (December 2020)

• Record Type: Journal Article
• Authors: Windle, Sean T.; Lane, Kristin D.; Gadalla, Nahla B.; Liu, Anna; Mu, Jianbing; Caleon, Ramoncito L.; Rahman, Rifat S.; Sá, Juliana M.; Wellems, Thomas E.
• Is Part Of: International journal for parasitology. Volume 14(2020)
• Page Start: 208
• Page End: 217
• Publication Date: 2020-12
• Subjects: Malaria -- Artemisinin-based combination chemotherapy -- Drug resistance -- Halofantrine -- Quantitative trait loci analysis; Parasitic diseases -- Chemotherapy -- Periodicals; Drug resistance -- Periodicals; 616.96061
• DOI: 10.1016/j.ijpddr.2020.10.009
• Languages: English
• ISSNs: 2211-3207

Abstract

Abstract: Background: Lumefantrine and mefloquine are used worldwide in artemisinin-based combination therapy (ACT) of malaria. Better understanding of drug susceptibility and resistance is needed and can be obtained from studies of genetic crosses. Methods: Drug response phenotypes of a cross between Plasmodium falciparum lines 803 (Cambodia) and GB4 (Ghana) were obtained as half-maximal effective concentrations (EC50 s) and days to recovery (DTR) after 24 h exposure to 500 nM lumefantrine. EC50 s of mefloquine, halofantrine, chloroquine, and dihydroartemisinin were also determined. Quantitative trait loci (QTL) analysis and statistical tests with candidate genes were used to identify polymorphisms associated with response phenotypes. Results: Lumefantrine EC50 s averaged 5.8-fold higher for the 803 than GB4 parent, and DTR results were 3–5 and 16–18 days, respectively. In 803 × GB4 progeny, outcomes of these two lumefantrine assays showed strong inverse correlation; these phenotypes also correlated strongly with mefloquine and halofantrine EC50 s. By QTL analysis, lumefantrine and mefloquine phenotypes mapped to a chromosome 5 region containing codon polymorphisms N86Y and Y184F in the P. falciparum multidrug resistance 1 protein (PfMDR1). Statistical tests of candidate genes identified correlations between inheritance of PfK13 Kelch protein polymorphism C580Y (and possibly K189T) and lumefantrine and mefloquine susceptibilities. Correlations were detected between lumefantrine and chloroquine EC50 s and polymorphisms N326S and I356T in the CVIET-type P. falciparum chloroquine resistance transporter (PfCRT) common to 803 and GB4. Conclusions: Correlations in this study suggest common mechanisms of action in lumefantrine, mefloquine, and halofantrine responses. PfK13 as well as PfMDR1 and PfCRT polymorphisms may affect access and/or action of these arylaminoalcohol drugs at locations of hemoglobin digestion and heme metabolism. In endemic regions, pressure from use of lumefantrine or mefloquine in ACTs may drive selection of PfK13 polymorphisms along with versions of PfMDR1 and PfCRT associated with lower susceptibility to these drugs. Graphical abstract: Image 1 Highlights: Two different lumefantrine response assays show inverse correlation in a P. falciparum cross. Lumefantrine, mefloquine, and halofantrine phenotypes correlate and may have pathways of action in common. Lumefantrine and mefloquine susceptibilities are linked to PfMDR1, PfCRT, and PfK13 polymorphisms. Lumefantrine and mefloquine in ACTs may drive selection of PfMDR1, PfCRT, and PfK13 polymorphisms including PfK13 580Y.