ChloroquineV1, France, Analysis, bibRecord, 000135

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

Identifieur interne : 000135 ( France/Analysis ); précédent : 000134; suivant : 000136

Mutations 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 [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 Llinas [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 ] ; 2015-09-30.

RBID : Hal:hal-01271612

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.

Url:

https://hal.sorbonne-universite.fr/hal-01271612

DOI: 10.1038/srep14552

Affiliations:

Australie, France, Royaume-Uni, États-Unis

Links toward previous steps (curation, corpus...)

to stream Hal, to step Corpus: 000168
to stream Hal, to step Curation: 000168
to stream Hal, to step Checkpoint: 000091
to stream Main, to step Merge: 000E45
to stream Main, to step Curation: 000E44
to stream Main, to step Exploration: 000E44
to stream France, to step Extraction: 000135

Links to Exploration step

Hal:hal-01271612

Le document en format XML

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            <ref type="url">http://www.cnrs.fr/</ref>
          </desc>
        </org>
</tutelle>
</tutelles>
</hal:affiliation>
<country>France</country>
</affiliation>
</author>
<author><name sortKey="Moore, Catherine M" sort="Moore, Catherine M" uniqKey="Moore C" first="Catherine M." last="Moore">Catherine M. Moore</name>
<affiliation wicri:level="1"><hal:affiliation type="institution" xml:id="struct-442694" status="VALID">          <orgName>University of London [London]</orgName>
          <desc>            <address>              <addrLine>Senate House, Malet St, London WC1E 7HU</addrLine>
              <country key="GB"></country>
            </address>
            <ref type="url">http://www.lon.ac.uk/</ref>
          </desc>
        </hal:affiliation>
<country>Royaume-Uni</country>
</affiliation>
</author>
<author><name sortKey="Daley, Daniel A" sort="Daley, Daniel A" uniqKey="Daley D" first="Daniel A." last="Daley">Daniel A. Daley</name>
<affiliation wicri:level="1"><hal:affiliation type="institution" xml:id="struct-10117" status="VALID">          <orgName>Old Dominion University [Norfolk]</orgName>
          <orgName type="acronym">ODU</orgName>
          <desc>            <address>              <addrLine>5115 Hampton Boulevard, Norfolk, VA 23529</addrLine>
              <country key="US"></country>
            </address>
            <ref type="url">http://www.odu.edu/</ref>
          </desc>
        </hal:affiliation>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Hoke, Matthew J" sort="Hoke, Matthew J" uniqKey="Hoke M" first="Matthew J." last="Hoke">Matthew J. Hoke</name>
<affiliation wicri:level="1"><hal:affiliation type="institution" xml:id="struct-10117" status="VALID">          <orgName>Old Dominion University [Norfolk]</orgName>
          <orgName type="acronym">ODU</orgName>
          <desc>            <address>              <addrLine>5115 Hampton Boulevard, Norfolk, VA 23529</addrLine>
              <country key="US"></country>
            </address>
            <ref type="url">http://www.odu.edu/</ref>
          </desc>
        </hal:affiliation>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Altenhofen, Lindsey M" sort="Altenhofen, Lindsey M" uniqKey="Altenhofen L" first="Lindsey M." last="Altenhofen">Lindsey M. Altenhofen</name>
<affiliation wicri:level="1"><hal:affiliation type="institution" xml:id="struct-115889" status="VALID">          <orgName>University of Pennsylvania [Philadelphia]</orgName>
          <desc>            <address>              <addrLine>3451 Walnut Street, Philadelphia, PA 19104 | 215-898-5000</addrLine>
              <country key="US"></country>
            </address>
            <ref type="url">http://www.upenn.edu/</ref>
          </desc>
        </hal:affiliation>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Painter, Heather J" sort="Painter, Heather J" uniqKey="Painter H" first="Heather J." last="Painter">Heather J. Painter</name>
<affiliation wicri:level="1"><hal:affiliation type="institution" xml:id="struct-115889" status="VALID">          <orgName>University of Pennsylvania [Philadelphia]</orgName>
          <desc>            <address>              <addrLine>3451 Walnut Street, Philadelphia, PA 19104 | 215-898-5000</addrLine>
              <country key="US"></country>
            </address>
            <ref type="url">http://www.upenn.edu/</ref>
          </desc>
        </hal:affiliation>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Mu, Jianbing" sort="Mu, Jianbing" uniqKey="Mu J" first="Jianbing" last="Mu">Jianbing Mu</name>
<affiliation wicri:level="1"><hal:affiliation type="regroupinstitution" xml:id="struct-100971" status="VALID">          <orgName>National Institutes of Health [Bethesda]</orgName>
          <orgName type="acronym">NIH</orgName>
          <desc>            <address>              <addrLine>9000 Rockville Pike, Bethesda, Maryland 20892</addrLine>
              <country key="US"></country>
            </address>
            <ref type="url">https://www.nih.gov/</ref>
          </desc>
        </hal:affiliation>
<country>États-Unis</country>
</affiliation>
</author>
<author><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>
<affiliation wicri:level="1"><hal:affiliation type="institution" xml:id="struct-302612" status="VALID">          <orgName>University of Oxford [Oxford]</orgName>
          <desc>            <address>              <addrLine>Wellington Square, Oxford OX1 2JD</addrLine>
              <country key="GB"></country>
            </address>
            <ref type="url">http://www.ox.ac.uk/</ref>
          </desc>
        </hal:affiliation>
<country>Royaume-Uni</country>
</affiliation>
</author>
<author><name sortKey="Llinas, Manuel" sort="Llinas, Manuel" uniqKey="Llinas M" first="Manuel" last="Llinas">Manuel Llinas</name>
<affiliation wicri:level="1"><hal:affiliation type="institution" xml:id="struct-115889" status="VALID">          <orgName>University of Pennsylvania [Philadelphia]</orgName>
          <desc>            <address>              <addrLine>3451 Walnut Street, Philadelphia, PA 19104 | 215-898-5000</addrLine>
              <country key="US"></country>
            </address>
            <ref type="url">http://www.upenn.edu/</ref>
          </desc>
        </hal:affiliation>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Martin, Rowena E" sort="Martin, Rowena E" uniqKey="Martin R" first="Rowena E." last="Martin">Rowena E. Martin</name>
<affiliation wicri:level="1"><hal:affiliation type="institution" xml:id="struct-74662" status="VALID">          <orgName>Australian National University</orgName>
          <orgName type="acronym">ANU</orgName>
          <desc>            <address>              <addrLine>The Australian National University Canberra ACT 0200 Australia</addrLine>
              <country key="AU"></country>
            </address>
            <ref type="url">http://www.anu.edu.au/index.php</ref>
          </desc>
        </hal:affiliation>
<country>Australie</country>
</affiliation>
</author>
<author><name sortKey="Fidock, David A" sort="Fidock, David A" uniqKey="Fidock D" first="David A" last="Fidock">David A. Fidock</name>
<affiliation wicri:level="1"><hal:affiliation type="institution" xml:id="struct-75524" status="VALID">          <orgName>Columbia University [New York]</orgName>
          <desc>            <address>              <addrLine>Columbia University in the City of New York 2960 Broadway New York, NY 10027-6902</addrLine>
              <country key="US"></country>
            </address>
            <ref type="url">http://www.columbia.edu/</ref>
          </desc>
        </hal:affiliation>
<country>États-Unis</country>
</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"><hal:affiliation type="institution" xml:id="struct-450228" status="VALID">          <idno type="ISNI">0000 0000 9826 3546</idno>
          <orgName>Dominican University of California</orgName>
          <desc>            <address>              <addrLine>50 Acacia Avenue, San Rafael, California 94901</addrLine>
              <country key="US"></country>
            </address>
            <ref type="url">https://home.dominican.edu/</ref>
          </desc>
        </hal:affiliation>
<country>États-Unis</country>
</affiliation>
</author>
<author><name sortKey="Krishna, Sanjeev" sort="Krishna, Sanjeev" uniqKey="Krishna S" first="Sanjeev" last="Krishna">Sanjeev Krishna</name>
<affiliation wicri:level="1"><hal:affiliation type="institution" xml:id="struct-442694" status="VALID">          <orgName>University of London [London]</orgName>
          <desc>            <address>              <addrLine>Senate House, Malet St, London WC1E 7HU</addrLine>
              <country key="GB"></country>
            </address>
            <ref type="url">http://www.lon.ac.uk/</ref>
          </desc>
        </hal:affiliation>
<country>Royaume-Uni</country>
</affiliation>
</author>
</analytic>
<idno type="DOI">10.1038/srep14552</idno>
<series><title level="j">Scientific Reports</title>
<idno type="ISSN">2045-2322</idno>
<imprint><date type="datePub">2015-09-30</date>
</imprint>
</series>
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<profileDesc><textClass></textClass>
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</teiHeader>
<front><div type="abstract" xml:lang="en">              <p>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.</p>
            </div>
</front>
</TEI>
<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>
</noRegion>
<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="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="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="Llinas">Manuel Llinas</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>
</noRegion>
</country>
</tree>
</affiliations>
</record>

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Serveur d'exploration Chloroquine

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

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

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