Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, enlarge the parasite’s food vacuole and alter drug sensitivities
Identifieur interne : 002B41 ( Ncbi/Checkpoint ); précédent : 002B40; suivant : 002B42Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, enlarge the parasite’s food vacuole and alter drug sensitivities
Auteurs : Serena Pulcini [Royaume-Uni] ; Henry M. Staines [Royaume-Uni] ; Andrew H. Lee [États-Unis] ; Sarah H. Shafik [Australie] ; Guillaume Bouyer [Royaume-Uni, France] ; Catherine M. Moore [Royaume-Uni] ; Daniel A. Daley [États-Unis] ; Matthew J. Hoke [États-Unis] ; Lindsey M. Altenhofen [États-Unis] ; Heather J. Painter [États-Unis] ; Jianbing Mu [États-Unis] ; David J. P. Ferguson [Royaume-Uni] ; Manuel Llinás [États-Unis] ; Rowena E. Martin [Australie] ; David A. Fidock [États-Unis] ; Roland A. Cooper [États-Unis] ; Sanjeev Krishna [Royaume-Uni]Source :
- Scientific Reports [ 2045-2322 ] ; 2015.
Descripteurs français
- KwdFr :
- Animaux, Antipaludiques (pharmacologie), Chloroquine (pharmacologie), Humains, Mutation, Ovocytes (métabolisme), Plasmodium falciparum (), Plasmodium falciparum (physiologie), Protéines de protozoaire (), Protéines de protozoaire (génétique), Protéines de transport membranaire (), Protéines de transport membranaire (génétique), Résistance aux substances (génétique), Substitution d'acide aminé, Tests de sensibilité parasitaire, Transport biologique, Vacuoles (métabolisme), Xenopus laevis.
- MESH :
- génétique : Protéines de protozoaire, Protéines de transport membranaire, Résistance aux substances.
- métabolisme : Ovocytes, Vacuoles.
- pharmacologie : Antipaludiques, Chloroquine.
- physiologie : Plasmodium falciparum.
- Animaux, Humains, Mutation, Plasmodium falciparum, Protéines de protozoaire, Protéines de transport membranaire, Substitution d'acide aminé, Tests de sensibilité parasitaire, Transport biologique, Xenopus laevis.
English descriptors
- KwdEn :
- Amino Acid Substitution, Animals, Antimalarials (pharmacology), Biological Transport, Chloroquine (pharmacology), Drug Resistance (genetics), Humans, Membrane Transport Proteins (chemistry), Membrane Transport Proteins (genetics), Mutation, Oocytes (metabolism), Parasitic Sensitivity Tests, Plasmodium falciparum (drug effects), Plasmodium falciparum (physiology), Protozoan Proteins (chemistry), Protozoan Proteins (genetics), Vacuoles (metabolism), Xenopus laevis.
- MESH :
- chemical , chemistry : Membrane Transport Proteins, Protozoan Proteins.
- chemical , genetics : Membrane Transport Proteins, Protozoan Proteins.
- chemical , pharmacology : Antimalarials, Chloroquine.
- drug effects : Plasmodium falciparum.
- genetics : Drug Resistance.
- metabolism : Oocytes, Vacuoles.
- physiology : Plasmodium falciparum.
- Amino Acid Substitution, Animals, Biological Transport, Humans, Mutation, Parasitic Sensitivity Tests, Xenopus laevis.
Abstract
Mutations in the
Url:
DOI: 10.1038/srep14552
PubMed: 26420308
PubMed Central: 4588581
Affiliations:
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Links to Exploration step
PMC:4588581Le document en format XML
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Mutations in the <italic>Plasmodium falciparum</italic>
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a10"><institution>Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center</institution>
, New York, NY 10032,<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Cooper, Roland A" sort="Cooper, Roland A" uniqKey="Cooper R" first="Roland A." last="Cooper">Roland A. Cooper</name>
<affiliation wicri:level="1"><nlm:aff id="a6"><institution>Department of Biological Sciences, Old Dominion University</institution>
, Norfolk, VA 23529,<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="a11"><institution>Department of Natural Sciences and Mathematics, Dominican University of California</institution>
, San Rafael, CA 94901,<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Krishna, Sanjeev" sort="Krishna, Sanjeev" uniqKey="Krishna S" first="Sanjeev" last="Krishna">Sanjeev Krishna</name>
<affiliation wicri:level="1"><nlm:aff id="a1"><institution>Institute for Infection and Immunity, St. George’s, University of London</institution>
, London SW17 0RE,<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series><title level="j">Scientific Reports</title>
<idno type="eISSN">2045-2322</idno>
<imprint><date when="2015">2015</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Substitution</term>
<term>Animals</term>
<term>Antimalarials (pharmacology)</term>
<term>Biological Transport</term>
<term>Chloroquine (pharmacology)</term>
<term>Drug Resistance (genetics)</term>
<term>Humans</term>
<term>Membrane Transport Proteins (chemistry)</term>
<term>Membrane Transport Proteins (genetics)</term>
<term>Mutation</term>
<term>Oocytes (metabolism)</term>
<term>Parasitic Sensitivity Tests</term>
<term>Plasmodium falciparum (drug effects)</term>
<term>Plasmodium falciparum (physiology)</term>
<term>Protozoan Proteins (chemistry)</term>
<term>Protozoan Proteins (genetics)</term>
<term>Vacuoles (metabolism)</term>
<term>Xenopus laevis</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term>
<term>Antipaludiques (pharmacologie)</term>
<term>Chloroquine (pharmacologie)</term>
<term>Humains</term>
<term>Mutation</term>
<term>Ovocytes (métabolisme)</term>
<term>Plasmodium falciparum ()</term>
<term>Plasmodium falciparum (physiologie)</term>
<term>Protéines de protozoaire ()</term>
<term>Protéines de protozoaire (génétique)</term>
<term>Protéines de transport membranaire ()</term>
<term>Protéines de transport membranaire (génétique)</term>
<term>Résistance aux substances (génétique)</term>
<term>Substitution d'acide aminé</term>
<term>Tests de sensibilité parasitaire</term>
<term>Transport biologique</term>
<term>Vacuoles (métabolisme)</term>
<term>Xenopus laevis</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Membrane Transport Proteins</term>
<term>Protozoan Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Membrane Transport Proteins</term>
<term>Protozoan Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antimalarials</term>
<term>Chloroquine</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Plasmodium falciparum</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Drug Resistance</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Protéines de protozoaire</term>
<term>Protéines de transport membranaire</term>
<term>Résistance aux substances</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Oocytes</term>
<term>Vacuoles</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Ovocytes</term>
<term>Vacuoles</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antipaludiques</term>
<term>Chloroquine</term>
</keywords>
<keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Plasmodium falciparum</term>
</keywords>
<keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Plasmodium falciparum</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Amino Acid Substitution</term>
<term>Animals</term>
<term>Biological Transport</term>
<term>Humans</term>
<term>Mutation</term>
<term>Parasitic Sensitivity Tests</term>
<term>Xenopus laevis</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Humains</term>
<term>Mutation</term>
<term>Plasmodium falciparum</term>
<term>Protéines de protozoaire</term>
<term>Protéines de transport membranaire</term>
<term>Substitution d'acide aminé</term>
<term>Tests de sensibilité parasitaire</term>
<term>Transport biologique</term>
<term>Xenopus laevis</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>Mutations in the <italic>Plasmodium falciparum</italic>
chloroquine resistance transporter, PfCRT, are the major determinant of chloroquine resistance in this lethal human malaria parasite. Here, we describe <italic>P. falciparum</italic>
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.</p>
</div>
</front>
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</analytic>
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<biblStruct><analytic><author><name sortKey="Cingolani, P" uniqKey="Cingolani P">P. Cingolani</name>
</author>
</analytic>
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<biblStruct><analytic><author><name sortKey="Abyzov, A" uniqKey="Abyzov A">A. Abyzov</name>
</author>
<author><name sortKey="Urban, A E" uniqKey="Urban A">A. E. Urban</name>
</author>
<author><name sortKey="Snyder, M" uniqKey="Snyder M">M. Snyder</name>
</author>
<author><name sortKey="Gerstein, M" uniqKey="Gerstein M">M. Gerstein</name>
</author>
</analytic>
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<biblStruct><analytic><author><name sortKey="Robinson, J T" uniqKey="Robinson J">J. T. Robinson</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Fidock, D A" uniqKey="Fidock D">D. A. Fidock</name>
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<author><name sortKey="Nomura, T" uniqKey="Nomura T">T. Nomura</name>
</author>
<author><name sortKey="Wellems, T E" uniqKey="Wellems T">T. E. Wellems</name>
</author>
</analytic>
</biblStruct>
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</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Broer, S" uniqKey="Broer S">S. Broer</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Broer, S" uniqKey="Broer S">S. Broer</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Schneider, C A" uniqKey="Schneider C">C. A. Schneider</name>
</author>
<author><name sortKey="Rasband, W S" uniqKey="Rasband W">W. S. Rasband</name>
</author>
<author><name sortKey="Eliceiri, K W" uniqKey="Eliceiri K">K. W. Eliceiri</name>
</author>
</analytic>
</biblStruct>
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</author>
<author><name sortKey="Callaghan, P S" uniqKey="Callaghan P">P. S. Callaghan</name>
</author>
<author><name sortKey="Roepe, P D" uniqKey="Roepe P">P. D. Roepe</name>
</author>
</analytic>
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<affiliations><list><country><li>Australie</li>
<li>France</li>
<li>Royaume-Uni</li>
<li>États-Unis</li>
</country>
</list>
<tree><country name="Royaume-Uni"><noRegion><name sortKey="Pulcini, Serena" sort="Pulcini, Serena" uniqKey="Pulcini S" first="Serena" last="Pulcini">Serena Pulcini</name>
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<name sortKey="Bouyer, Guillaume" sort="Bouyer, Guillaume" uniqKey="Bouyer G" first="Guillaume" last="Bouyer">Guillaume Bouyer</name>
<name sortKey="Ferguson, David J P" sort="Ferguson, David J P" uniqKey="Ferguson D" first="David J. P." last="Ferguson">David J. P. Ferguson</name>
<name sortKey="Krishna, Sanjeev" sort="Krishna, Sanjeev" uniqKey="Krishna S" first="Sanjeev" last="Krishna">Sanjeev Krishna</name>
<name sortKey="Moore, Catherine M" sort="Moore, Catherine M" uniqKey="Moore C" first="Catherine M." last="Moore">Catherine M. Moore</name>
<name sortKey="Staines, Henry M" sort="Staines, Henry M" uniqKey="Staines H" first="Henry M." last="Staines">Henry M. Staines</name>
</country>
<country name="États-Unis"><noRegion><name sortKey="Lee, Andrew H" sort="Lee, Andrew H" uniqKey="Lee A" first="Andrew H." last="Lee">Andrew H. Lee</name>
</noRegion>
<name sortKey="Altenhofen, Lindsey M" sort="Altenhofen, Lindsey M" uniqKey="Altenhofen L" first="Lindsey M." last="Altenhofen">Lindsey M. Altenhofen</name>
<name sortKey="Cooper, Roland A" sort="Cooper, Roland A" uniqKey="Cooper R" first="Roland A." last="Cooper">Roland A. Cooper</name>
<name sortKey="Cooper, Roland A" sort="Cooper, Roland A" uniqKey="Cooper R" first="Roland A." last="Cooper">Roland A. Cooper</name>
<name sortKey="Daley, Daniel A" sort="Daley, Daniel A" uniqKey="Daley D" first="Daniel A." last="Daley">Daniel A. Daley</name>
<name sortKey="Fidock, David A" sort="Fidock, David A" uniqKey="Fidock D" first="David A." last="Fidock">David A. Fidock</name>
<name sortKey="Fidock, David A" sort="Fidock, David A" uniqKey="Fidock D" first="David A." last="Fidock">David A. Fidock</name>
<name sortKey="Hoke, Matthew J" sort="Hoke, Matthew J" uniqKey="Hoke M" first="Matthew J." last="Hoke">Matthew J. Hoke</name>
<name sortKey="Llinas, Manuel" sort="Llinas, Manuel" uniqKey="Llinas M" first="Manuel" last="Llinás">Manuel Llinás</name>
<name sortKey="Mu, Jianbing" sort="Mu, Jianbing" uniqKey="Mu J" first="Jianbing" last="Mu">Jianbing Mu</name>
<name sortKey="Painter, Heather J" sort="Painter, Heather J" uniqKey="Painter H" first="Heather J." last="Painter">Heather J. Painter</name>
</country>
<country name="Australie"><noRegion><name sortKey="Shafik, Sarah H" sort="Shafik, Sarah H" uniqKey="Shafik S" first="Sarah H." last="Shafik">Sarah H. Shafik</name>
</noRegion>
<name sortKey="Martin, Rowena E" sort="Martin, Rowena E" uniqKey="Martin R" first="Rowena E." last="Martin">Rowena E. Martin</name>
</country>
<country name="France"><noRegion><name sortKey="Bouyer, Guillaume" sort="Bouyer, Guillaume" uniqKey="Bouyer G" first="Guillaume" last="Bouyer">Guillaume Bouyer</name>
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<name sortKey="Bouyer, Guillaume" sort="Bouyer, Guillaume" uniqKey="Bouyer G" first="Guillaume" last="Bouyer">Guillaume Bouyer</name>
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</affiliations>
</record>
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