Expansion of a Specific <named-content content-type="genus-species">Plasmodium falciparum</named-content> PfMDR1 Haplotype in Southeast Asia with Increased Substrate Transport

ABSTRACT Artemisinin-based combination therapies (ACTs) have been vital in reducing malaria mortality rates since the 2000s. Their efficacy, however, is threatened by the emergence and spread of artemisinin resistance in Southeast Asia. The Plasmodium falciparum multidrug resistance protein 1 (PfMDR...

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Autores principales:	Carla Calçada, Miguel Silva, Vitória Baptista, Vandana Thathy, Rita Silva-Pedrosa, Diana Granja, Pedro Eduardo Ferreira, José Pedro Gil, David A. Fidock, Maria Isabel Veiga
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	malaria Plasmodium falciparum pfmdr1 antimalarial drug resistance copy number variation Y184F mutation Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/80cc9d4af3af401ca60fa59365c9cf21
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spelling	oai:doaj.org-article:80cc9d4af3af401ca60fa59365c9cf212021-11-15T15:55:43ZExpansion of a Specific <named-content content-type="genus-species">Plasmodium falciparum</named-content> PfMDR1 Haplotype in Southeast Asia with Increased Substrate Transport10.1128/mBio.02093-202150-7511https://doaj.org/article/80cc9d4af3af401ca60fa59365c9cf212020-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02093-20https://doaj.org/toc/2150-7511ABSTRACT Artemisinin-based combination therapies (ACTs) have been vital in reducing malaria mortality rates since the 2000s. Their efficacy, however, is threatened by the emergence and spread of artemisinin resistance in Southeast Asia. The Plasmodium falciparum multidrug resistance protein 1 (PfMDR1) transporter plays a central role in parasite resistance to ACT partner drugs through gene copy number variations (CNV) and/or single nucleotide polymorphisms (SNPs). Using genomic epidemiology, we show that multiple pfmdr1 copies encoding the N86 and 184F haplotype are prevalent across Southeast Asia. Applying genome editing tools on the Southeast Asian Dd2 strain and using a surrogate assay to measure transporter activity in infected red blood cells, we demonstrate that parasites harboring multicopy N86/184F PfMDR1 have a higher Fluo-4 transport capacity compared with those expressing the wild-type N86/Y184 haplotype. Multicopy N86/184F PfMDR1 is also associated with decreased parasite susceptibility to lumefantrine. These findings provide evidence of the geographic selection and expansion of specific multicopy PfMDR1 haplotypes associated with multidrug resistance in Southeast Asia. IMPORTANCE Global efforts to eliminate malaria depend on the continued success of artemisinin-based combination therapies (ACTs) that target Plasmodium asexual blood-stage parasites. Resistance to ACTs, however, has emerged, creating the need to define the underlying mechanisms. Mutations in the P. falciparum multidrug resistance protein 1 (PfMDR1) transporter constitute an important determinant of resistance. Applying gene editing tools combined with an analysis of a public database containing thousands of parasite genomes, we show geographic selection and expansion of a pfmdr1 gene amplification encoding the N86/184F haplotype in Southeast Asia. Parasites expressing this PfMDR1 variant possess a higher transport capacity that modulates their responses to antimalarials. These data could help tailor and optimize antimalarial drug usage in different regions where malaria is endemic by taking into account the regional prevalence of pfmdr1 polymorphisms.Carla CalçadaMiguel SilvaVitória BaptistaVandana ThathyRita Silva-PedrosaDiana GranjaPedro Eduardo FerreiraJosé Pedro GilDavid A. FidockMaria Isabel VeigaAmerican Society for MicrobiologyarticlemalariaPlasmodium falciparumpfmdr1antimalarial drug resistancecopy number variationY184F mutationMicrobiologyQR1-502ENmBio, Vol 11, Iss 6 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	malaria Plasmodium falciparum pfmdr1 antimalarial drug resistance copy number variation Y184F mutation Microbiology QR1-502
spellingShingle	malaria Plasmodium falciparum pfmdr1 antimalarial drug resistance copy number variation Y184F mutation Microbiology QR1-502 Carla Calçada Miguel Silva Vitória Baptista Vandana Thathy Rita Silva-Pedrosa Diana Granja Pedro Eduardo Ferreira José Pedro Gil David A. Fidock Maria Isabel Veiga Expansion of a Specific <named-content content-type="genus-species">Plasmodium falciparum</named-content> PfMDR1 Haplotype in Southeast Asia with Increased Substrate Transport
description	ABSTRACT Artemisinin-based combination therapies (ACTs) have been vital in reducing malaria mortality rates since the 2000s. Their efficacy, however, is threatened by the emergence and spread of artemisinin resistance in Southeast Asia. The Plasmodium falciparum multidrug resistance protein 1 (PfMDR1) transporter plays a central role in parasite resistance to ACT partner drugs through gene copy number variations (CNV) and/or single nucleotide polymorphisms (SNPs). Using genomic epidemiology, we show that multiple pfmdr1 copies encoding the N86 and 184F haplotype are prevalent across Southeast Asia. Applying genome editing tools on the Southeast Asian Dd2 strain and using a surrogate assay to measure transporter activity in infected red blood cells, we demonstrate that parasites harboring multicopy N86/184F PfMDR1 have a higher Fluo-4 transport capacity compared with those expressing the wild-type N86/Y184 haplotype. Multicopy N86/184F PfMDR1 is also associated with decreased parasite susceptibility to lumefantrine. These findings provide evidence of the geographic selection and expansion of specific multicopy PfMDR1 haplotypes associated with multidrug resistance in Southeast Asia. IMPORTANCE Global efforts to eliminate malaria depend on the continued success of artemisinin-based combination therapies (ACTs) that target Plasmodium asexual blood-stage parasites. Resistance to ACTs, however, has emerged, creating the need to define the underlying mechanisms. Mutations in the P. falciparum multidrug resistance protein 1 (PfMDR1) transporter constitute an important determinant of resistance. Applying gene editing tools combined with an analysis of a public database containing thousands of parasite genomes, we show geographic selection and expansion of a pfmdr1 gene amplification encoding the N86/184F haplotype in Southeast Asia. Parasites expressing this PfMDR1 variant possess a higher transport capacity that modulates their responses to antimalarials. These data could help tailor and optimize antimalarial drug usage in different regions where malaria is endemic by taking into account the regional prevalence of pfmdr1 polymorphisms.
format	article
author	Carla Calçada Miguel Silva Vitória Baptista Vandana Thathy Rita Silva-Pedrosa Diana Granja Pedro Eduardo Ferreira José Pedro Gil David A. Fidock Maria Isabel Veiga
author_facet	Carla Calçada Miguel Silva Vitória Baptista Vandana Thathy Rita Silva-Pedrosa Diana Granja Pedro Eduardo Ferreira José Pedro Gil David A. Fidock Maria Isabel Veiga
author_sort	Carla Calçada
title	Expansion of a Specific <named-content content-type="genus-species">Plasmodium falciparum</named-content> PfMDR1 Haplotype in Southeast Asia with Increased Substrate Transport
title_short	Expansion of a Specific <named-content content-type="genus-species">Plasmodium falciparum</named-content> PfMDR1 Haplotype in Southeast Asia with Increased Substrate Transport
title_full	Expansion of a Specific <named-content content-type="genus-species">Plasmodium falciparum</named-content> PfMDR1 Haplotype in Southeast Asia with Increased Substrate Transport
title_fullStr	Expansion of a Specific <named-content content-type="genus-species">Plasmodium falciparum</named-content> PfMDR1 Haplotype in Southeast Asia with Increased Substrate Transport
title_full_unstemmed	Expansion of a Specific <named-content content-type="genus-species">Plasmodium falciparum</named-content> PfMDR1 Haplotype in Southeast Asia with Increased Substrate Transport
title_sort	expansion of a specific <named-content content-type="genus-species">plasmodium falciparum</named-content> pfmdr1 haplotype in southeast asia with increased substrate transport
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/80cc9d4af3af401ca60fa59365c9cf21
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Expansion of a Specific <named-content content-type="genus-species">Plasmodium falciparum</named-content> PfMDR1 Haplotype in Southeast Asia with Increased Substrate Transport

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