bioRxiv : the preprint server for biology · 2023
Mapping the genomic landscape of multidrug resistance in Plasmodium falciparum and its impact on parasite fitness.
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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
Аннотация
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.