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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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2020-12-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.02093-20 |
| _version_ | 1831592183711399936 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-18T01:37:39Z |
| format | Article |
| id | doaj.art-80cc9d4af3af401ca60fa59365c9cf21 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-18T01:37:39Z |
| publishDate | 2020-12-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-80cc9d4af3af401ca60fa59365c9cf212022-12-21T21:25:24ZengAmerican Society for MicrobiologymBio2150-75112020-12-0111610.1128/mBio.02093-20Expansion of a Specific <named-content content-type="genus-species">Plasmodium falciparum</named-content> PfMDR1 Haplotype in Southeast Asia with Increased Substrate TransportCarla Calçada0Miguel Silva1Vitória Baptista2Vandana Thathy3Rita Silva-Pedrosa4Diana Granja5Pedro Eduardo Ferreira6José Pedro Gil7David A. Fidock8Maria Isabel Veiga9Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, Braga, PortugalLife and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, Braga, PortugalLife and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, Braga, PortugalDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York, USALife and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, Braga, PortugalLife and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, Braga, PortugalLife and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, Braga, PortugalStockholm Malaria Center, Department of Microbiology and Tumour Cell Biology, Karolinska Institutet, Stockholm, SwedenDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York, USALife and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, Braga, PortugalABSTRACT 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.https://journals.asm.org/doi/10.1128/mBio.02093-20malariaPlasmodium falciparumpfmdr1antimalarial drug resistancecopy number variationY184F mutation |
| spellingShingle | 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 mBio malaria Plasmodium falciparum pfmdr1 antimalarial drug resistance copy number variation Y184F mutation |
| 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_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_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_sort | expansion of a specific named content content type genus species plasmodium falciparum named content pfmdr1 haplotype in southeast asia with increased substrate transport |
| topic | malaria Plasmodium falciparum pfmdr1 antimalarial drug resistance copy number variation Y184F mutation |
| url | https://journals.asm.org/doi/10.1128/mBio.02093-20 |
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