Genetic background determines allele-specific Pfkelch13-mediated artemisinin tolerance and persistence in Plasmodium falciparum
- 1Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
Abstract
Artemisinin-based combination therapies are the frontline treatment for Plasmodium falciparum malaria, but their efficacy is threatened by Artemisinin partial resistance (ARTR). ARTR 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 ARTR receptivity using the ring-stage survival assay (RSA), a proxy for clinical resistance. We demonstrate that ARTR 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.
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BibTeX
@misc{ullah2026genetic,
title = {{Genetic background determines allele-specific Pfkelch13-mediated artemisinin tolerance and persistence in Plasmodium falciparum}},
author = {I. Ullah and M. C. Martin and D. Ndiaye and S. K. Volkman and D. F. Wirth},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.03.749253},
url = {https://www.biorxiv.org/content/10.64898/2026.09.03.749253v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Genetic background determines allele-specific Pfkelch13-mediated artemisinin tolerance and persistence in Plasmodium falciparum
AU - I. Ullah
AU - M. C. Martin
AU - D. Ndiaye
AU - S. K. Volkman
AU - D. F. Wirth
PY - 2026
DA - 2026/09/03
PB - bioRxiv
DO - 10.64898/2026.09.03.749253
UR - https://www.biorxiv.org/content/10.64898/2026.09.03.749253v1
AB - Artemisinin-based combination therapies are the frontline treatment for Plasmodium falciparum malaria, but their efficacy is threatened by Artemisinin partial resistance (ARTR). ARTR 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 ARTR receptivity using the ring-stage survival assay (RSA), a proxy for clinical resistance. We demonstrate that ARTR 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.
ER -