Metabolic QTL analysis links chloroquine resistance in Plasmodium falciparum to impaired hemoglobin catabolism

• Published in: PLoS genetics Vol. 10; no. 1; p. e1004085
• Main Authors: Lewis, Ian A, Wacker, Mark, Olszewski, Kellen L, Cobbold, Simon A, Baska, Katelynn S, Tan, Asako, Ferdig, Michael T, Llinás, Manuel
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.01.2014; Public Library of Science (PLoS)
• Subjects: Antimalarials - therapeutic use; Biology; Chloroquine - therapeutic use; Chromosome Mapping; Drug Resistance - genetics; Genetic aspects; Genetic research; Genomics; Health aspects; Hemoglobin; Hemoglobins - genetics; Hemoglobins - metabolism; Humans; Malaria; Malaria, Falciparum - drug therapy; Malaria, Falciparum - genetics; Malaria, Falciparum - parasitology; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Metabolism - genetics; Metabolites; Microbiological research; Parasites; Peptides - genetics; Peptides - isolation & purification; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - genetics; Protozoan Proteins - genetics; Protozoan Proteins - metabolism; Quantitative trait loci; Quantitative Trait Loci - genetics; Israel
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1004085

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.