Genetic background determines allele-specific Pfkelch13- mediated artemisinin tolerance and persistence in Plasmodium falciparum
Abstract
Artemisinin-based combination therapies are the frontline treatment for Plasmodium falciparum malaria, but their efficacy is threatened by Artemisinin partial resistance (ART R ). ART R in Plasmodium falciparum is mediated by Pfkelch13 ( k13 ) mutations but remains rare in West Africa. A critical question is whether short-term drug survival intrinsically predicts long-term evolutionary persistence. Here, using CRISPR-Cas9 editing, and nanopore-assisted allele tracking in a contemporary Senegalese isolate, we evaluated ART R receptivity using the ring-stage survival assay (RSA), a proxy for clinical resistance. We demonstrate that ART R survival and drug-free persistence are biologically separable traits. While the WHO-validated Asian I543T mutation conferred the RSA phenotype, it was rapidly counter-selected during drug-free growth. In contrast, emerging African alleles (R561H, M579I) and a regional novel variant (C473S) establish stable resistance without a competitive penalty. These findings reveal that a parasite’s genetic background acts as a strict evolutionary filter, uncoupling short-term tolerance from long-term persistence and establishing that genomic context determines allele-specific resistance trajectories.
Related
- Efficacy of artemisinin derivatives and kelch13 mutations in Plasmodium falciparum: a systematic review and meta-analysis
- First Detection of WHO-validated artemisinin resistance Plasmodium falciparum K13 C469Y mutation in patient from Senegal.
- Spatial surveillance of Plasmodium falciparum Kelch 13 mutations reveals High-Frequency A675V and the First Molecular Evidence of Suspected Partial Artemisinin Resistance in Baringo in Kenya.
- Association between Plasmodium falciparum Kelch13 mutations and malaria parasite clearance half-life after artemisinin-based therapy: an updated WWARN systematic review and individual patient data meta-analysis
- Acute Pancreatitis as a Rare Complication of Plasmodium falciparum Malaria: A Case Report
BibTeX
@misc{ullah2026genetic,
title = {{Genetic background determines allele-specific Pfkelch13- mediated artemisinin tolerance and persistence in Plasmodium falciparum}},
author = {Imran Ullah and Morgan C. Martin and Daouda Ndiaye and Sarah K. Volkman and Dyann F. Wirth},
howpublished = {Research Square},
year = {2026},
month = oct,
doi = {10.21203/rs.3.rs-11221098/v1},
url = {https://doi.org/10.21203/rs.3.rs-11221098/v1},
note = {CC BY 4.0},
}
RIS
TY - UNPB
TI - Genetic background determines allele-specific Pfkelch13- mediated artemisinin tolerance and persistence in Plasmodium falciparum
AU - Imran Ullah
AU - Morgan C. Martin
AU - Daouda Ndiaye
AU - Sarah K. Volkman
AU - Dyann F. Wirth
PY - 2026
DA - 2026/10/27
PB - Research Square
DO - 10.21203/rs.3.rs-11221098/v1
UR - https://doi.org/10.21203/rs.3.rs-11221098/v1
AB - Artemisinin-based combination therapies are the frontline treatment for Plasmodium falciparum malaria, but their efficacy is threatened by Artemisinin partial resistance (ART R ). ART R in Plasmodium falciparum is mediated by Pfkelch13 ( k13 ) mutations but remains rare in West Africa. A critical question is whether short-term drug survival intrinsically predicts long-term evolutionary persistence. Here, using CRISPR-Cas9 editing, and nanopore-assisted allele tracking in a contemporary Senegalese isolate, we evaluated ART R receptivity using the ring-stage survival assay (RSA), a proxy for clinical resistance. We demonstrate that ART R survival and drug-free persistence are biologically separable traits. While the WHO-validated Asian I543T mutation conferred the RSA phenotype, it was rapidly counter-selected during drug-free growth. In contrast, emerging African alleles (R561H, M579I) and a regional novel variant (C473S) establish stable resistance without a competitive penalty. These findings reveal that a parasite’s genetic background acts as a strict evolutionary filter, uncoupling short-term tolerance from long-term persistence and establishing that genomic context determines allele-specific resistance trajectories.
SN - 2693-5015
ER -