title: Metabolic QTL analysis links chloroquine resistance in Plasmodium falciparum to impaired hemoglobin catabolism.
abstract: Drug resistant strains of the malaria parasite, Plasmodium falciparum, have rendered chloroquine ineffective throughout much of the world. In parts of Africa and Asia, the coordinated shift from chloroquine to other drugs has resulted in the near disappearance of chloroquine-resistant (CQR) parasites from the population. Currently, there is no molecular explanation for this phenomenon. Herein, we employ metabolic quantitative trait locus mapping (mQTL) to analyze progeny from a genetic cross between chloroquine-susceptible (CQS) and CQR parasites. We identify a family of hemoglobin-derived peptides that are elevated in CQR parasites and show that peptide accumulation, drug resistance, and reduced parasite fitness are all linked in vitro to CQR alleles of the P. falciparum chloroquine resistance transporter (pfcrt). These findings suggest that CQR parasites are less fit because mutations in pfcrt interfere with hemoglobin digestion by the parasite. Moreover, our findings may provide a molecular explanation for the reemergence of CQS parasites in wild populations.
authors.affiliation: Department of Molecular Biology and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Lewis
authors.affiliation: Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Wacker
authors.affiliation: Department of Molecular Biology and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America.
authors.forename: Kellen L
authors.initials: KL
authors.lastname: Olszewski
authors.affiliation: Department of Molecular Biology and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Cobbold
authors.affiliation: Department of Molecular Biology and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America.
authors.forename: Katelynn S
authors.initials: KS
authors.lastname: Baska
authors.affiliation: Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United States of America.
authors.forename: Asako
authors.initials: A
authors.lastname: Tan
authors.affiliation: Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United States of America.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Ferdig
authors.affiliation: Department of Molecular Biology and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, United States of America.
authors.forename: Manuel
authors.initials: M
authors.lastname: Llinás
mesh_terms: D000962:Antimalarials / Q000627:therapeutic use; D002738:Chloroquine / Q000627:therapeutic use*; D002874:Chromosome Mapping; D004351:Drug Resistance / Q000235:genetics; D006454:Hemoglobins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000235:genetics / Q000469:parasitology; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008660:Metabolism / Q000235:genetics; D010455:Peptides / Q000235:genetics / Q000302:isolation & purification; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D040641:Quantitative Trait Loci / Q000235:genetics*
chemical_list: D000962:Antimalarials; D006454:Hemoglobins; D026901:Membrane Transport Proteins; D010455:Peptides; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; D002738:Chloroquine