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Article
Chloroquine Susceptibility and Reversibility in a Plasmodium falciparum Genetic Cross
Molecular Microbiology
  • Jigar J. Patel, The Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame
  • Drew Thacker, The Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame
  • Jon C. Tan, The Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame
  • Perri Pleeter, Departments of Chemistry, and of Biochemistry and Cellular & Molecular Biology, Georgetown University
  • Lisa Checkley, The Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame
  • Joseph M. Gonzales, The Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame
  • Bingbing Deng, The Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame
  • Paul D. Roepe, Departments of Chemistry, and of Biochemistry and Cellular & Molecular Biology, Georgetown University
  • Roland A. Cooper, Departments of Chemistry, and of Biochemistry and Cellular & Molecular Biology, Georgetown University
  • Michael T. Ferdig, The Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame
Document Type
Article
Publication Date
11-1-2010
Disciplines
Department
Natural Sciences and Mathematics
Abstract

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 Southeast Asiaderived 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 labeling of purified recombinant PfMDR1 protein with a highly specific photoaffinity CQ analogue, and lack of competition for photolabeling 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.

Publisher Statement
Originally published as Patel, J. J., Thacker, D., Tan, J. C., Pleeter, P., Checkley, L., Gonzales, J. M., ... & Ferdig, M. T. (2010). Chloroquine susceptibility and reversibility in a Plasmodium falciparum genetic cross. Molecular microbiology, 78(3), 770-787.
Citation Information
Jigar J. Patel, Drew Thacker, Jon C. Tan, Perri Pleeter, et al.. "Chloroquine Susceptibility and Reversibility in a Plasmodium falciparum Genetic Cross" Molecular Microbiology Vol. 78 Iss. 3 (2010) p. 770 - 787 ISSN: 1365-2958
Available at: http://works.bepress.com/roland_cooper/28/