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

Research output: Contribution to journalArticle

42 Citations (Scopus)

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 1 2014

Fingerprint

chloroquine
catabolism
Chloroquine
Plasmodium falciparum
hemoglobin
quantitative trait loci
parasite
Hemoglobins
Parasites
metabolism
parasites
peptide
drug
Genetic Crosses
drug resistance
transporters
analysis
malaria
Peptides
peptides

All Science Journal Classification (ASJC) codes

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

Cite this

Lewis, Ian A. ; Wacker, Mark ; Olszewski, Kellen L. ; Cobbold, Simon A. ; Baska, Katelynn S. ; Tan, Asako ; Ferdig, Michael T. ; Llinás, Manuel. / Metabolic QTL Analysis Links Chloroquine Resistance in Plasmodium falciparum to Impaired Hemoglobin Catabolism. In: PLoS genetics. 2014 ; Vol. 10, No. 1.
@article{a35c145654bc4f618aa8f5feb0606620,
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.",
author = "Lewis, {Ian A.} and Mark Wacker and Olszewski, {Kellen L.} and Cobbold, {Simon A.} and Baska, {Katelynn S.} and Asako Tan and Ferdig, {Michael T.} and Manuel Llin{\'a}s",
year = "2014",
month = "1",
day = "1",
doi = "10.1371/journal.pgen.1004085",
language = "English (US)",
volume = "10",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "1",

}

Metabolic QTL Analysis Links Chloroquine Resistance in Plasmodium falciparum to Impaired Hemoglobin Catabolism. / Lewis, Ian A.; Wacker, Mark; Olszewski, Kellen L.; Cobbold, Simon A.; Baska, Katelynn S.; Tan, Asako; Ferdig, Michael T.; Llinás, Manuel.

In: PLoS genetics, Vol. 10, No. 1, e1004085, 01.01.2014.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Metabolic QTL Analysis Links Chloroquine Resistance in Plasmodium falciparum to Impaired Hemoglobin Catabolism

AU - Lewis, Ian A.

AU - Wacker, Mark

AU - Olszewski, Kellen L.

AU - Cobbold, Simon A.

AU - Baska, Katelynn S.

AU - Tan, Asako

AU - Ferdig, Michael T.

AU - Llinás, Manuel

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84896724410&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84896724410&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1004085

DO - 10.1371/journal.pgen.1004085

M3 - Article

C2 - 24391526

AN - SCOPUS:84896724410

VL - 10

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 1

M1 - e1004085

ER -