Title

Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, enlarge the parasite's food vacuole and alter drug sensitivities

Authors

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 CaliforniaFollow
Sanjeev Krishna, Institute for Infection and Immunity, St. George's, University of London

Document Type

Article

Source

Scientific Reports

ISSN

2045-2322

Volume

5

Publication Date

9-30-2015

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.

Rights

Copyright © 2015 The Author(s)

PubMed ID

26420308

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.