Expansion of a specific plasmodium falciparum PfMDR1 Haplotype in southeast Asia with increased substrate transport
Autor(a) principal: | |
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Data de Publicação: | 2020 |
Outros Autores: | , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | https://hdl.handle.net/1822/70933 |
Resumo: | 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. |
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Expansion of a specific plasmodium falciparum PfMDR1 Haplotype in southeast Asia with increased substrate transportmalariaPlasmodium falciparumpfmdr1antimalarial drug resistancecopy number variationY184FmutationY184F mutationScience & TechnologyArtemisinin-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.This work was funded by Portuguese National funds through the Foundation for Science and Technology (FCT) (project UIDB/50026/2020 and UIDP/50026/2020; fellowships PD/BD/127826/2016 to C.C., SFRH/BD/129769/2017 to M.S., SFRH/BD/145427/2019 to V.B., SFRH/BD/131540/2017 to R.S.P., and IF/00143/2015/CP1294/CT0001 to P.E.F. and contract funding to M.I.V. provided through DL 57/2016 [CRP]); by the projects NORTE-01-0145-FEDER-000013, NORTE-01-0145-FEDER-000023, and NORTE 01-0145-FEDER-028178, supported by Norte Portugal Regional Operational Program (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the Euro pean Regional Development Fund (ERDF); by the Institute Merieux through “Starting” Mérieux Research Grant 2016 to M.I.V.; by the ESCMID to P.E.F. and by the NIH R01 AI109023 and R37AI50234 to D.A.F.info:eu-repo/semantics/publishedVersionAmerican Society for MicrobiologyUniversidade do MinhoCalçada, Carla Sofia MartinsSilva, MiguelBaptista, VitóriaThathy, VandanaPedrosa, AnaGranja, DianaFerreira, Pedro EduardoGil, José PedroFidock, David A.Veiga, Maria Isabel2020-122020-12-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/1822/70933engCalçada, Carla; Silva, Miguel; Baptista, Vitória; Thathy, Vandana; Pedrosa, Ana; Granja, Diana; Ferreira, Pedro Eduardo; Gil, José Pedro; Fidock, David A.; Veiga, Maria Isabel, Expansion of a Specific Plasmodium falciparum PfMDR1 Haplotype in Southeast Asia with Increased Substrate Transport. mBio, 11(6), e02093-20, 20202161-212910.1128/mBio.02093-2033262257http://mbio.asm.org/info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-02-10T01:18:46Zoai:repositorium.sdum.uminho.pt:1822/70933Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:56:09.418956Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Expansion of a specific plasmodium falciparum PfMDR1 Haplotype in southeast Asia with increased substrate transport |
title |
Expansion of a specific plasmodium falciparum PfMDR1 Haplotype in southeast Asia with increased substrate transport |
spellingShingle |
Expansion of a specific plasmodium falciparum PfMDR1 Haplotype in southeast Asia with increased substrate transport Calçada, Carla Sofia Martins malaria Plasmodium falciparum pfmdr1 antimalarial drug resistance copy number variation Y184F mutation Y184F mutation Science & Technology |
title_short |
Expansion of a specific plasmodium falciparum PfMDR1 Haplotype in southeast Asia with increased substrate transport |
title_full |
Expansion of a specific plasmodium falciparum PfMDR1 Haplotype in southeast Asia with increased substrate transport |
title_fullStr |
Expansion of a specific plasmodium falciparum PfMDR1 Haplotype in southeast Asia with increased substrate transport |
title_full_unstemmed |
Expansion of a specific plasmodium falciparum PfMDR1 Haplotype in southeast Asia with increased substrate transport |
title_sort |
Expansion of a specific plasmodium falciparum PfMDR1 Haplotype in southeast Asia with increased substrate transport |
author |
Calçada, Carla Sofia Martins |
author_facet |
Calçada, Carla Sofia Martins Silva, Miguel Baptista, Vitória Thathy, Vandana Pedrosa, Ana Granja, Diana Ferreira, Pedro Eduardo Gil, José Pedro Fidock, David A. Veiga, Maria Isabel |
author_role |
author |
author2 |
Silva, Miguel Baptista, Vitória Thathy, Vandana Pedrosa, Ana Granja, Diana Ferreira, Pedro Eduardo Gil, José Pedro Fidock, David A. Veiga, Maria Isabel |
author2_role |
author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade do Minho |
dc.contributor.author.fl_str_mv |
Calçada, Carla Sofia Martins Silva, Miguel Baptista, Vitória Thathy, Vandana Pedrosa, Ana Granja, Diana Ferreira, Pedro Eduardo Gil, José Pedro Fidock, David A. Veiga, Maria Isabel |
dc.subject.por.fl_str_mv |
malaria Plasmodium falciparum pfmdr1 antimalarial drug resistance copy number variation Y184F mutation Y184F mutation Science & Technology |
topic |
malaria Plasmodium falciparum pfmdr1 antimalarial drug resistance copy number variation Y184F mutation Y184F mutation Science & Technology |
description |
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. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020-12 2020-12-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
https://hdl.handle.net/1822/70933 |
url |
https://hdl.handle.net/1822/70933 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Calçada, Carla; Silva, Miguel; Baptista, Vitória; Thathy, Vandana; Pedrosa, Ana; Granja, Diana; Ferreira, Pedro Eduardo; Gil, José Pedro; Fidock, David A.; Veiga, Maria Isabel, Expansion of a Specific Plasmodium falciparum PfMDR1 Haplotype in Southeast Asia with Increased Substrate Transport. mBio, 11(6), e02093-20, 2020 2161-2129 10.1128/mBio.02093-20 33262257 http://mbio.asm.org/ |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
dc.publisher.none.fl_str_mv |
American Society for Microbiology |
publisher.none.fl_str_mv |
American Society for Microbiology |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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