Identification of a mutant PfCRT-mediated chloroquine tolerance phenotype in Plasmodium falciparum.

Mutant forms of the Plasmodium falciparum transporter PfCRT constitute the key determinant of parasite resistance to chloroquine (CQ), the former first-line antimalarial, and are ubiquitous to infections that fail CQ treatment. However, treatment can often be successful in individuals harboring muta...

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Autores principales:	Stephanie G Valderramos, Juan-Carlos Valderramos, Lise Musset, Lisa A Purcell, Odile Mercereau-Puijalon, Eric Legrand, David A Fidock
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/4a22e5d7f9e44459ae244d4b5f675e31
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spelling	oai:doaj.org-article:4a22e5d7f9e44459ae244d4b5f675e312021-12-02T20:00:41ZIdentification of a mutant PfCRT-mediated chloroquine tolerance phenotype in Plasmodium falciparum.1553-73661553-737410.1371/journal.ppat.1000887https://doaj.org/article/4a22e5d7f9e44459ae244d4b5f675e312010-05-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20485514/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Mutant forms of the Plasmodium falciparum transporter PfCRT constitute the key determinant of parasite resistance to chloroquine (CQ), the former first-line antimalarial, and are ubiquitous to infections that fail CQ treatment. However, treatment can often be successful in individuals harboring mutant pfcrt alleles, raising questions about the role of host immunity or pharmacokinetics vs. the parasite genetic background in contributing to treatment outcomes. To examine whether the parasite genetic background dictates the degree of mutant pfcrt-mediated CQ resistance, we replaced the wild type pfcrt allele in three CQ-sensitive strains with mutant pfcrt of the 7G8 allelic type prevalent in South America, the Oceanic region and India. Recombinant clones exhibited strain-dependent CQ responses that ranged from high-level resistance to an incremental shift that did not meet CQ resistance criteria. Nonetheless, even in the most susceptible clones, 7G8 mutant pfcrt enabled parasites to tolerate CQ pressure and recrudesce in vitro after treatment with high concentrations of CQ. 7G8 mutant pfcrt was found to significantly impact parasite responses to other antimalarials used in artemisinin-based combination therapies, in a strain-dependent manner. We also report clinical isolates from French Guiana that harbor mutant pfcrt, identical or related to the 7G8 haplotype, and manifest a CQ tolerance phenotype. One isolate, H209, harbored a novel PfCRT C350R mutation and demonstrated reduced quinine and artemisinin susceptibility. Our data: 1) suggest that high-level CQR is a complex biological process dependent on the presence of mutant pfcrt; 2) implicate a role for variant pfcrt alleles in modulating parasite susceptibility to other clinically important antimalarials; and 3) uncover the existence of a phenotype of CQ tolerance in some strains harboring mutant pfcrt.Stephanie G ValderramosJuan-Carlos ValderramosLise MussetLisa A PurcellOdile Mercereau-PuijalonEric LegrandDavid A FidockPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 6, Iss 5, p e1000887 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Stephanie G Valderramos Juan-Carlos Valderramos Lise Musset Lisa A Purcell Odile Mercereau-Puijalon Eric Legrand David A Fidock Identification of a mutant PfCRT-mediated chloroquine tolerance phenotype in Plasmodium falciparum.
description	Mutant forms of the Plasmodium falciparum transporter PfCRT constitute the key determinant of parasite resistance to chloroquine (CQ), the former first-line antimalarial, and are ubiquitous to infections that fail CQ treatment. However, treatment can often be successful in individuals harboring mutant pfcrt alleles, raising questions about the role of host immunity or pharmacokinetics vs. the parasite genetic background in contributing to treatment outcomes. To examine whether the parasite genetic background dictates the degree of mutant pfcrt-mediated CQ resistance, we replaced the wild type pfcrt allele in three CQ-sensitive strains with mutant pfcrt of the 7G8 allelic type prevalent in South America, the Oceanic region and India. Recombinant clones exhibited strain-dependent CQ responses that ranged from high-level resistance to an incremental shift that did not meet CQ resistance criteria. Nonetheless, even in the most susceptible clones, 7G8 mutant pfcrt enabled parasites to tolerate CQ pressure and recrudesce in vitro after treatment with high concentrations of CQ. 7G8 mutant pfcrt was found to significantly impact parasite responses to other antimalarials used in artemisinin-based combination therapies, in a strain-dependent manner. We also report clinical isolates from French Guiana that harbor mutant pfcrt, identical or related to the 7G8 haplotype, and manifest a CQ tolerance phenotype. One isolate, H209, harbored a novel PfCRT C350R mutation and demonstrated reduced quinine and artemisinin susceptibility. Our data: 1) suggest that high-level CQR is a complex biological process dependent on the presence of mutant pfcrt; 2) implicate a role for variant pfcrt alleles in modulating parasite susceptibility to other clinically important antimalarials; and 3) uncover the existence of a phenotype of CQ tolerance in some strains harboring mutant pfcrt.
format	article
author	Stephanie G Valderramos Juan-Carlos Valderramos Lise Musset Lisa A Purcell Odile Mercereau-Puijalon Eric Legrand David A Fidock
author_facet	Stephanie G Valderramos Juan-Carlos Valderramos Lise Musset Lisa A Purcell Odile Mercereau-Puijalon Eric Legrand David A Fidock
author_sort	Stephanie G Valderramos
title	Identification of a mutant PfCRT-mediated chloroquine tolerance phenotype in Plasmodium falciparum.
title_short	Identification of a mutant PfCRT-mediated chloroquine tolerance phenotype in Plasmodium falciparum.
title_full	Identification of a mutant PfCRT-mediated chloroquine tolerance phenotype in Plasmodium falciparum.
title_fullStr	Identification of a mutant PfCRT-mediated chloroquine tolerance phenotype in Plasmodium falciparum.
title_full_unstemmed	Identification of a mutant PfCRT-mediated chloroquine tolerance phenotype in Plasmodium falciparum.
title_sort	identification of a mutant pfcrt-mediated chloroquine tolerance phenotype in plasmodium falciparum.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/4a22e5d7f9e44459ae244d4b5f675e31
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Identification of a mutant PfCRT-mediated chloroquine tolerance phenotype in Plasmodium falciparum.

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