Mapping the genomic landscape of multidrug resistance in <i>Plasmodium falciparum</i> and its impact on parasite fitness.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 37939186.
- Also identified by DOI 10.1126/sciadv.adi2364 and PMC identifier 10631731.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Drug-resistant <i>Plasmodium falciparum</i> parasites have swept across Southeast Asia and now threaten Africa. By implementing a <i>P. falciparum</i> 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 <i>k13</i> as the central mediator of ART resistance in vitro and identified secondary markers. Applying bulk segregant analysis, quantitative trait loci mapping using 34 recombinant haplotypes, 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.
Medical subject headings
- Parasites
- Malaria, Falciparum