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Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, enlarge the parasite's food vacuole and alter drug sensitivities
Scientific Reports
  • Serena Pulcini, Institute for Infection and Immunity, St. George's, University of London
  • Henry M. Staines, Institute for Infection and Immunity, St. George's, University of London
  • Andrew H. Lee, Department of Microbiology and Immunology, Columbia University Medical Center
  • Sarah H. Shafik, Research School of Biology, Australian National University
  • Guillaume Bouyer, Institute for Infection and Immunity, St. George's, University of London
  • Catherine M. Moore, Institute for Infection and Immunity, St. George's, University of London
  • Daniel A. Daley, Department of Biological Sciences, Old Dominion University
  • Matthew J Hoke, Department of Biological Sciences, Old Dominion University
  • Lindsey M. Altenhofen, Department of Biochemistry and Molecular Biology and Center for Malaria Research, Pennsylvania State University
  • Heather J. Painter, Department of Biochemistry and Molecular Biology and Center for Malaria Research, Pennsylvania State University
  • Jianbing Mu, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health
  • David J. P. Ferguson, Nuffield Department of Clinical Laboratory Sciences, University of Oxford
  • Manuel Llinas, Department of Biochemistry and Molecular Biology and Center for Malaria Research, Pennsylvania State University
  • Rowen E. Martin, Research School of Biology, Australian National University
  • David A. Fidock, Department of Microbiology and Immunology, Columbia University Medical Center
  • Roland Cooper, Department of Natural Sciences and Mathematics, Dominican University of California
  • Sanjeev Krishna, Institute for Infection and Immunity, St. George's, University of London
Document Type
Article
Publication Date
9-30-2015
Disciplines
Department
Natural Sciences and Mathematics
Abstract

Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, are the major determinant of chloroquine resistance in this lethal human malaria parasite. Here, we describe P. falciparum lines subjected to selection by amantadine or blasticidin that carry PfCRT mutations (C101F or L272F), causing the development of enlarged food vacuoles. These parasites also have increased sensitivity to chloroquine and some other quinoline antimalarials, but exhibit no or minimal change in sensitivity to artemisinins, when compared with parental strains. A transgenic parasite line expressing the L272F variant of PfCRT confirmed this increased chloroquine sensitivity and enlarged food vacuole phenotype. Furthermore, the introduction of the C101F or L272F mutation into a chloroquine-resistant variant of PfCRT reduced the ability of this protein to transport chloroquine by approximately 93 and 82%, respectively, when expressed in Xenopus oocytes. These data provide, at least in part, a mechanistic explanation for the increased sensitivity of the mutant parasite lines to chloroquine. Taken together, these findings provide new insights into PfCRT function and PfCRT-mediated drug resistance, as well as the food vacuole, which is an important target of many antimalarial drugs.

Publisher Statement
Originally published as Pulcini, S., Staines, H. M., Lee, A. H., Shafik, S. H., Bouyer, G., Moore, C. M., ... & Krishna, S. (2015). Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, enlarge the parasite’s food vacuole and alter drug sensitivities. Scientific reports, 5.
Citation Information
Serena Pulcini, Henry M. Staines, Andrew H. Lee, Sarah H. Shafik, et al.. "Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, enlarge the parasite's food vacuole and alter drug sensitivities" Scientific Reports Vol. 5 (2015) ISSN: 2045-2322
Available at: http://works.bepress.com/roland_cooper/33/