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Mapping the genomic landscape of multidrug resistance in Plasmodium falciparum and its impact on parasite fitness
Drug-resistant Plasmodium falciparum parasites have swept across Southeast Asia and now threaten Africa. By implementing a P. falciparum genetic cross using humanized mice, we report the identification of key determinants of resistance to artemisinin (ART) and piperaquine (PPQ) in the dominant Asian...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10312498/ https://www.ncbi.nlm.nih.gov/pubmed/37398288 http://dx.doi.org/10.1101/2023.06.02.543338 |
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author | Mok, Sachel Yeo, Tomas Hong, Davin Shears, Melanie J. Ross, Leila S. Ward, Kurt E. Dhingra, Satish K. Kanai, Mariko Bridgford, Jessica L. Tripathi, Abhai K. Mlambo, Godfree Burkhard, Anna Y. Fairhurst, Kate J. Gil-Iturbe, Eva Park, Heekuk Rozenberg, Felix D. Kim, Jonathan Mancia, Filippo Quick, Matthias Uhlemann, Anne-Catrin Sinnis, Photini Fidock, David A. |
author_facet | Mok, Sachel Yeo, Tomas Hong, Davin Shears, Melanie J. Ross, Leila S. Ward, Kurt E. Dhingra, Satish K. Kanai, Mariko Bridgford, Jessica L. Tripathi, Abhai K. Mlambo, Godfree Burkhard, Anna Y. Fairhurst, Kate J. Gil-Iturbe, Eva Park, Heekuk Rozenberg, Felix D. Kim, Jonathan Mancia, Filippo Quick, Matthias Uhlemann, Anne-Catrin Sinnis, Photini Fidock, David A. |
author_sort | Mok, Sachel |
collection | PubMed |
description | Drug-resistant Plasmodium falciparum parasites have swept across Southeast Asia and now threaten Africa. By implementing a P. falciparum genetic cross using humanized mice, we report the identification of key determinants of resistance to artemisinin (ART) and piperaquine (PPQ) in the dominant Asian KEL1/PLA1 lineage. We mapped k13 as the central mediator of ART resistance and identified secondary markers. Applying bulk segregant analysis, quantitative trait loci mapping and gene editing, our data reveal an epistatic interaction between mutant PfCRT and multicopy plasmepsins 2/3 in mediating high-grade PPQ resistance. Susceptibility and parasite fitness assays implicate PPQ as a driver of selection for KEL1/PLA1 parasites. Mutant PfCRT enhanced susceptibility to lumefantrine, the first-line partner drug in Africa, highlighting a potential benefit of opposing selective pressures with this drug and PPQ. We also identified that the ABCI3 transporter can operate in concert with PfCRT and plasmepsins 2/3 in mediating multigenic resistance to antimalarial agents. |
format | Online Article Text |
id | pubmed-10312498 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
spelling | pubmed-103124982023-07-01 Mapping the genomic landscape of multidrug resistance in Plasmodium falciparum and its impact on parasite fitness Mok, Sachel Yeo, Tomas Hong, Davin Shears, Melanie J. Ross, Leila S. Ward, Kurt E. Dhingra, Satish K. Kanai, Mariko Bridgford, Jessica L. Tripathi, Abhai K. Mlambo, Godfree Burkhard, Anna Y. Fairhurst, Kate J. Gil-Iturbe, Eva Park, Heekuk Rozenberg, Felix D. Kim, Jonathan Mancia, Filippo Quick, Matthias Uhlemann, Anne-Catrin Sinnis, Photini Fidock, David A. bioRxiv Article Drug-resistant Plasmodium falciparum parasites have swept across Southeast Asia and now threaten Africa. By implementing a P. falciparum genetic cross using humanized mice, we report the identification of key determinants of resistance to artemisinin (ART) and piperaquine (PPQ) in the dominant Asian KEL1/PLA1 lineage. We mapped k13 as the central mediator of ART resistance and identified secondary markers. Applying bulk segregant analysis, quantitative trait loci mapping and gene editing, our data reveal an epistatic interaction between mutant PfCRT and multicopy plasmepsins 2/3 in mediating high-grade PPQ resistance. Susceptibility and parasite fitness assays implicate PPQ as a driver of selection for KEL1/PLA1 parasites. Mutant PfCRT enhanced susceptibility to lumefantrine, the first-line partner drug in Africa, highlighting a potential benefit of opposing selective pressures with this drug and PPQ. We also identified that the ABCI3 transporter can operate in concert with PfCRT and plasmepsins 2/3 in mediating multigenic resistance to antimalarial agents. Cold Spring Harbor Laboratory 2023-06-03 /pmc/articles/PMC10312498/ /pubmed/37398288 http://dx.doi.org/10.1101/2023.06.02.543338 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator. |
spellingShingle | Article Mok, Sachel Yeo, Tomas Hong, Davin Shears, Melanie J. Ross, Leila S. Ward, Kurt E. Dhingra, Satish K. Kanai, Mariko Bridgford, Jessica L. Tripathi, Abhai K. Mlambo, Godfree Burkhard, Anna Y. Fairhurst, Kate J. Gil-Iturbe, Eva Park, Heekuk Rozenberg, Felix D. Kim, Jonathan Mancia, Filippo Quick, Matthias Uhlemann, Anne-Catrin Sinnis, Photini Fidock, David A. Mapping the genomic landscape of multidrug resistance in Plasmodium falciparum and its impact on parasite fitness |
title | Mapping the genomic landscape of multidrug resistance in Plasmodium falciparum and its impact on parasite fitness |
title_full | Mapping the genomic landscape of multidrug resistance in Plasmodium falciparum and its impact on parasite fitness |
title_fullStr | Mapping the genomic landscape of multidrug resistance in Plasmodium falciparum and its impact on parasite fitness |
title_full_unstemmed | Mapping the genomic landscape of multidrug resistance in Plasmodium falciparum and its impact on parasite fitness |
title_short | Mapping the genomic landscape of multidrug resistance in Plasmodium falciparum and its impact on parasite fitness |
title_sort | mapping the genomic landscape of multidrug resistance in plasmodium falciparum and its impact on parasite fitness |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10312498/ https://www.ncbi.nlm.nih.gov/pubmed/37398288 http://dx.doi.org/10.1101/2023.06.02.543338 |
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