Mapping the genomic landscape of multidrug resistance in Plasmodium falciparum and its impact on parasite fitness
Year: 2023
Type: article
Abstract: 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.
Source: Science Advances
Authors: Sachel Mok, Tomas Yeo, Davin Hong, Melanie J. Shears, Leila S. Ross, Kurt E. Ward, Satish K. Dhingra, Mariko Kanai, Jessica L. Bridgford, Abhai K. Tripathi, Godfree Mlambo, Anna Y. Burkhard, Megan R. Ansbro, Kate J. Fairhurst, Eva Gil-Iturbe, Heekuk Park, Felix D. Rozenberg, Jonathan Kim, Filippo Mancia, Rick M. Fairhurst, Matthias Quick, Anne-Catrin Uhlemann, Photini Sinnis, David A. Fidock
Language: English
Topic: Malaria Research and Control
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,576
Awards: Role of pfcrt in chloroquine resistance in P. falciparum, G1873888087, G2228175059, G2622379494, Deciphering the role of Plasmodium falciparum plasmepsin 2/3 amplifications in mutant pfcrt-driven piperaquine resistance, The Skin Phase of Malaria Infection, G4664701975, G6022860391, G6369331463, G8398908363, Leveraging PfCRT Structure to Discern Function and Predict Emergence of Drug-Resistant Malaria, Defining the Role of PfCRT and PfMDR1 as Pleiotropic Mediators of Plasmodium falciparum Multidrug Resistance, Elucidating the molecular basis of piperaquine resistance in Plasmodium falciparum, Defining P. falciparum resistance to artemisinin-based combination therapies
OpenAlex ID: W4388507715