Structural polymorphism in the promoter of pfmrp2 confers Plasmodium falciparum tolerance to quinoline drugs

Abstract

Drug resistance in Plasmodium falciparum remains a challenge for the malaria eradication programmes around the world. With the emergence of artemisinin resistance, the efficacy of the partner drugs in the artemisinin combination therapies (ACT) that include quinoline-based drugs is becoming critical. So far only few resistance markers have been identified from which only two transmembrane transporters namely PfMDR1 (an ATP-binding cassette transporter) and PfCRT (a drug-metabolite transporter) have been experimentally verified. Another P. falciparum transporter, the ATP-binding cassette containing multidrug resistance-associated protein (PfMRP2) represents an additional possible factor of drug resistance in P. falciparum. In this study, we identified a parasite clone that is derived from the 3D7 P. falciparum strain and shows increased resistance to chloroquine, mefloquine and quinine through the trophozoite and schizont stages. We demonstrate that the resistance phenotype is caused by a 4.1 kb deletion in the 5′ upstream region of the pfmrp2 gene that leads to an alteration in the pfmrp2 transcription and thus increased level of PfMRP2 protein. These results also suggest the importance of putative promoter elements in regulation of gene expression during the P. falciparum intra-erythrocytic developmental cycle and the potential of genetic polymorphisms within these regions to underlie drug resistance.

Complex Polymorphisms in the Plasmodium falciparum Multidrug Resistance Protein 2 Gene and Its Contribution to Antimalarial Response

“…It is conceivable that these variations alter the steady-state conformations of the cytoplasmic regions of the protein and with that, the interaction with the antimalarial drugs, affecting their efflux out of the parasite. The proposed potential role of PfMRP2 in the drug response to CQ and MQ is further supported by the recent DNA microarray-based observations that associated Pfmrp2 promoter polymorphisms with the parasite CQ and MQ responses in vitro (20).…”

“…Lastly, recent microarray-based approaches have identified a P. falciparum 3D7 subvariant which carries a ca. 4-kb deletion at the Pfmrp2 5= putative promoter that is associated with decreased susceptibility to CQ and MQ (20).…”

Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia

“…To date, descriptions of transcriptional modification in Plasmodium sp. appear to be limited to associations with genomic structural variants, for example, gene amplification as in pfmdr1 and deletions or repeatlength polymorphisms in promoter regions (57,58). One could hypothesize that SNPs in an AP2 transcription factor DNAbinding domain may alter its motif binding and stage-specific expression of downstream genes.…”

Indels, structural variation, and recombination drive genomic diversity in Plasmodium falciparum

“…There has been no comprehensive survey of insertion/deletion (indel) variation in P. falciparum, although there is evidence that indels may be unusually abundant (Su and Wellems 1996;Jeffares et al 2007;Tan et al 2010;Haerty and Golding 2011). Little is known about variation in noncoding regions, which could have a significant impact on phenotype by regulating gene expression (Gonzales et al 2008;Mok et al 2014). Knowledge of complex variation, where haplotypes are highly diverged from the reference genome, is constrained to a few wellstudied genes such as msp1 (Roy et al 2008).…”