Metabolic QTL Analysis Links Chloroquine Resistance in Plasmodium falciparum to Impaired Hemoglobin Catabolism

Ian A. Lewis, Mark Wacker, Kellen L. Olszewski, Simon A. Cobbold, Katelynn S. Baska, Asako Tan, Michael T. Ferdig, Manuel Llinás

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48 Scopus citations

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.

Original languageEnglish (US)
Article numbere1004085
JournalPLoS genetics
Volume10
Issue number1
DOIs
StatePublished - Jan 2014

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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    Lewis, I. A., Wacker, M., Olszewski, K. L., Cobbold, S. A., Baska, K. S., Tan, A., Ferdig, M. T., & Llinás, M. (2014). Metabolic QTL Analysis Links Chloroquine Resistance in Plasmodium falciparum to Impaired Hemoglobin Catabolism. PLoS genetics, 10(1), [e1004085]. https://doi.org/10.1371/journal.pgen.1004085