Chloroquine susceptibility and reversibility in a Plasmodium falciparum genetic cross.
Mutations in the Plasmodium falciparum chloroquine (CQ) resistance transporter (PfCRT) are major determinants of verapamil (VP)-reversible CQ resistance (CQR). In the presence of mutant PfCRT, additional genes contribute to the wide range of CQ susceptibilities observed. It is not known if these genes influence mechanisms of chemosensitization by CQR reversal agents. Using quantitative trait locus (QTL) mapping of progeny clones from the HB3 × Dd2 cross, we show that the P. falciparum multidrug resistance gene 1 (pfmdr1) interacts with the South-East Asia-derived mutant pfcrt haplotype to modulate CQR levels. A novel chromosome 7 locus is predicted to contribute with the pfcrt and pfmdr1 loci to influence CQR levels. Chemoreversal via a wide range of chemical structures operates through a direct pfcrt-based mechanism. Direct inhibition of parasite growth by these reversal agents is influenced by pfcrt mutations and additional loci. Direct labelling of purified recombinant PfMDR1 protein with a highly specific photoaffinity CQ analogue, and lack of competition for photolabelling by VP, supports our QTL predictions. We find no evidence that pfmdr1 copy number affects CQ response in the progeny; however, inheritance patterns indicate that an allele-specific interaction between pfmdr1 and pfcrt is part of the complex genetic background of CQR.
Patel
Jigar J
JJ
The Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, 205 Galvin Life Sciences, Notre Dame, IN 46556, USA.
Thacker
Drew
D
Tan
John C
JC
Pleeter
Perri
P
Checkley
Lisa
L
Gonzales
Joseph M
JM
Deng
Bingbing
B
Roepe
Paul D
PD
Cooper
Roland A
RA
Ferdig
Michael T
MT
D000962:Antimalarials / Q000494:pharmacology; D002738:Chloroquine / Q000494:pharmacology*; D004351:Drug Resistance; D018628:Gene Dosage; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D040641:Quantitative Trait Loci; D014700:Verapamil / Q000494:pharmacology
D000962:Antimalarials; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; D002738:Chloroquine; D014700:Verapamil
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