Evidence for Regulation of Hemoglobin Metabolism and Intracellular Ionic Flux by the Plasmodium falciparum Chloroquine Resistance Transporter

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dc.contributor.authorLee, Andrew H.en
dc.contributor.authorDhingra, Satish K.en
dc.contributor.authorLewis, Ian A.en
dc.contributor.authorSingh, Maneesh K.en
dc.contributor.authorSiriwardana, Amilaen
dc.contributor.authorDalal, Seemaen
dc.contributor.authorRubiano, Kellyen
dc.contributor.authorKlein, Matthias S.en
dc.contributor.authorBaska, Katelynn S.en
dc.contributor.authorKrishna, Sanjeeven
dc.contributor.authorKlemba, Michaelen
dc.contributor.authorRoepe, Paul D.en
dc.contributor.authorLlinas, Manuelen
dc.contributor.authorGarcia, Celia R. S.en
dc.contributor.authorFidock, David A.en
dc.contributor.departmentBiochemistryen
dc.date.accessioned2018-12-07T20:25:04Zen
dc.date.available2018-12-07T20:25:04Zen
dc.date.issued2018-09-11en
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
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).en
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]en
dc.format.extent13 pagesen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1038/s41598-018-31715-9en
dc.identifier.issn2045-2322en
dc.identifier.other13578en
dc.identifier.pmid30206341en
dc.identifier.urihttp://hdl.handle.net/10919/86270en
dc.identifier.volume8en
dc.language.isoenen
dc.publisherSpringer Natureen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectmalaria parasitesen
dc.subjectdigestive-vacuoleen
dc.subjectdrug-resistanceen
dc.subjectinfected erythrocytesen
dc.subjectantimalarial-drugsen
dc.subjectpfcrt mutationsen
dc.subjectprotein pfcrten
dc.subjectfood vacuoleen
dc.subjectin-vivoen
dc.subjecth+ leaken
dc.titleEvidence for Regulation of Hemoglobin Metabolism and Intracellular Ionic Flux by the Plasmodium falciparum Chloroquine Resistance Transporteren
dc.title.serialScientific Reportsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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