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dc.contributor.authorLee, Andrew H.
dc.contributor.authorDhingra, Satish K.
dc.contributor.authorLewis, Ian A.
dc.contributor.authorSingh, Maneesh K.
dc.contributor.authorSiriwardana, Amila
dc.contributor.authorDalal, Seema
dc.contributor.authorRubiano, Kelly
dc.contributor.authorKlein, Matthias S.
dc.contributor.authorBaska, Katelynn S.
dc.contributor.authorKrishna, Sanjeev
dc.contributor.authorKlemba, Michael
dc.contributor.authorRoepe, Paul D.
dc.contributor.authorLlinas, Manuel
dc.contributor.authorGarcia, Celia R. S.
dc.contributor.authorFidock, David A.
dc.date.accessioned2018-12-07T20:25:04Z
dc.date.available2018-12-07T20:25:04Z
dc.date.issued2018-09-11
dc.identifier.issn2045-2322
dc.identifier.other13578
dc.identifier.urihttp://hdl.handle.net/10919/86270
dc.description.abstractPlasmodium falciparum multidrug resistance constitutes a major obstacle to the global malaria elimination campaign. Specific mutations in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) mediate resistance to the 4-aminoquinoline drug chloroquine and impact parasite susceptibility to several partner agents used in current artemisinin-based combination therapies, including amodiaquine. By examining gene-edited parasites, we report that the ability of the widespread Dd2 PfCRT isoform to mediate chloroquine and amodiaquine resistance is substantially reduced by the addition of the PfCRT L272F mutation, which arose under blasticidin selection. We also provide evidence that L272F confers a significant fitness cost to asexual blood stage parasites. Studies with amino acid-restricted media identify this mutant as a methionine auxotroph. Metabolomic analysis also reveals an accumulation of short, hemoglobin-derived peptides in the Dd2 + L272F and Dd2 isoforms, compared with parasites expressing wild-type PfCRT. Physiologic studies with the ionophores monensin and nigericin support an impact of PfCRT isoforms on Ca2+ release, with substantially reduced Ca2+ levels observed in Dd2 + L272F parasites. Our data reveal a central role for PfCRT in regulating hemoglobin catabolism, amino acid availability, and ionic balance in P. falciparum, in addition to its role in determining parasite susceptibility to heme-binding 4-aminoquinoline drugs.en_US
dc.description.sponsorshipNIH [R01 AI05234, R01 AI124678, R01 AI506312]; FAPESP [2011/51295-5]; Alberta Innovates; Canada Foundation for Innovation [CFIJELF 34986]; Natural Sciences and Engineering Research Council (NSERC) [04547]; Burroughs Wellcome Fund (Investigators in Pathogenesis of Infectious Disease Award for Research); NIH Director's New Innovators Award [1DP2OD001315]; Center for Quantitative Biology [P50 GM071508]
dc.format.extent13 pages
dc.format.mimetypeapplication/pdf
dc.language.isoen_US
dc.publisherSpringer Nature
dc.rightsCreative Commons Attribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectmalaria parasites
dc.subjectdigestive-vacuole
dc.subjectdrug-resistance
dc.subjectinfected erythrocytes
dc.subjectantimalarial-drugs
dc.subjectpfcrt mutations
dc.subjectprotein pfcrt
dc.subjectfood vacuole
dc.subjectin-vivo
dc.subjecth+ leak
dc.titleEvidence for Regulation of Hemoglobin Metabolism and Intracellular Ionic Flux by the Plasmodium falciparum Chloroquine Resistance Transporteren_US
dc.typeArticle - Refereed
dc.description.notesPartial funding for this work was provided by the NIH to DAF (R01 AI05234 and R01 AI124678) and PDR (R01 AI506312). Funding to CRSG was provided by FAPESP (process 2011/51295-5). MS is a CAPES fellow. IAL and MSK are funded by Alberta Innovates (Translational Heath Chair); Canada Foundation for Innovation (CFIJELF 34986); and the Natural Sciences and Engineering Research Council (NSERC, Discovery Grant 04547). ML was supported by the Burroughs Wellcome Fund (Investigators in Pathogenesis of Infectious Disease Award for Research), an NIH Director's New Innovators Award (1DP2OD001315), and the Center for Quantitative Biology (P50 GM071508).
dc.title.serialScientific Reports
dc.identifier.doihttps://doi.org/10.1038/s41598-018-31715-9
dc.identifier.volume8
dc.type.dcmitypeText
dc.identifier.pmid30206341


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