Skip navigation
Skip navigation

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

Pulcini, Serena; Staines, Henry M; Lee, Andrew H; Shafik, Sarah; Bouyer, Guilherme; Moore, Catherine M; Daley, Daniel A.; Hoke, Matthew J.; Altenhofen, Lindsey M.; Painter, Heather J.; Mu, Jianbing; Ferguson, David J.P.; Llinas, Manuel; Martin, Rowena; Fidock, David A; Cooper, Ronald A.; Krishna, Sanjeev

Description

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...[Show more]

dc.contributor.authorPulcini, Serena
dc.contributor.authorStaines, Henry M
dc.contributor.authorLee, Andrew H
dc.contributor.authorShafik, Sarah
dc.contributor.authorBouyer, Guilherme
dc.contributor.authorMoore, Catherine M
dc.contributor.authorDaley, Daniel A.
dc.contributor.authorHoke, Matthew J.
dc.contributor.authorAltenhofen, Lindsey M.
dc.contributor.authorPainter, Heather J.
dc.contributor.authorMu, Jianbing
dc.contributor.authorFerguson, David J.P.
dc.contributor.authorLlinas, Manuel
dc.contributor.authorMartin, Rowena
dc.contributor.authorFidock, David A
dc.contributor.authorCooper, Ronald A.
dc.contributor.authorKrishna, Sanjeev
dc.date.accessioned2016-02-24T22:41:10Z
dc.identifier.issn2045-2322
dc.identifier.urihttp://hdl.handle.net/1885/98589
dc.description.abstractMutations 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.
dc.publisherNature Publishing Group
dc.rightsAuthor/s retain copyright
dc.sourceScientific Reports
dc.titleMutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, enlarge the parasite's food vacuole and alter drug sensitivities
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume5
dc.date.issued2015
local.identifier.absfor060500 - MICROBIOLOGY
local.identifier.absfor110707 - Innate Immunity
local.identifier.absfor110904 - Neurology and Neuromuscular Diseases
local.identifier.ariespublicationU3488905xPUB6136
local.type.statusPublished Version
local.contributor.affiliationPulcini, Serena, Univeristy of London
local.contributor.affiliationStaines, Henry M, University of London
local.contributor.affiliationLee, Andrew H, Columbia University Medical Center
local.contributor.affiliationShafik, Sarah, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationBouyer, Guilherme, University of London
local.contributor.affiliationMoore, Catherine M, University of London
local.contributor.affiliationDaley, Daniel A., Old Dominion University
local.contributor.affiliationHoke, Matthew J., Old Dominion University
local.contributor.affiliationAltenhofen, Lindsey M., Pennsylvania State University
local.contributor.affiliationPainter, Heather J., Pennsylvania State University
local.contributor.affiliationMu, Jianbing, National Institutes of Health
local.contributor.affiliationFerguson, David J.P., University of Oxford
local.contributor.affiliationLlinas, Manuel, Pennsylvania State University
local.contributor.affiliationMartin, Rowena, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationFidock, David A, Columbia University Medical Center
local.contributor.affiliationCooper, Ronald A., Dominican University of California
local.contributor.affiliationKrishna, Sanjeev, St. George's Hospital Medical School
local.bibliographicCitation.startpage1
local.bibliographicCitation.lastpage16
local.identifier.doi10.1038/srep14552
dc.date.updated2016-02-24T10:09:55Z
local.identifier.scopusID2-s2.0-84942844889
dcterms.accessRightsOpen Access
CollectionsANU Research Publications

Download

File Description SizeFormat Image
01_Pulcini_Mutations_in_the_Plasmodium_2015.pdf1.31 MBAdobe PDF


Items in Open Research are protected by copyright, with all rights reserved, unless otherwise indicated.

Updated:  19 May 2020/ Responsible Officer:  University Librarian/ Page Contact:  Library Systems & Web Coordinator