Single-cell transcriptional changes of artemisinin-sensitive K13C580 and artemisinin-resistant K13580YPlasmodium falciparum upon dihydroartemisinin exposure
Year: 2026
Type: article
Abstract: , driven by mutations in the Kelch13 (K13) gene, threatens these gains. To investigate the molecular basis of this resistance, we applied single-cell RNA sequencing to coisogenic parasite lines, K13 wild-type (K13-C580) and the artemisinin-resistant mutant (K13-580Y), following a 6 hour pulse of dihydroartemisinin (DHA). This approach enabled high-resolution profiling across all intraerythrocytic stages. Both lines exhibited stage-specific transcriptional responses, with the most pronounced changes in ring and trophozoite stages. These included downregulation of metabolic genes and upregulation of stress response pathways, including the unfolded protein response and protein trafficking. Transcriptional signatures consistent with a dormancy-like state were observed, particularly in the downregulation of SERA family genes. Notably, K13-580Y parasites showed a more consistent and robust transcriptional adaptation across stages, suggesting enhanced survival under drug-induced stress. Using MELD, a computational framework for quantifying transcriptional perturbation, we found that K13-580Y parasites exhibited higher DHA likelihood scores across the asexual cycle, indicating broad and sustained transcriptional shifts in response to treatment. Additionally, increased expression of surface proteins such as PfEMP1 and GARP was observed in K13-580Y parasites at baseline and following DHA exposure. Functional assays confirmed that anti-GARP antibodies retained efficacy against both lines, supporting its potential as a therapeutic target. These findings provide a comprehensive view of the cellular responses that may facilitate artemisinin resistance, identify molecular features of dormancy and pathogenesis, and highlight surface proteins like GARP and PfEMP1 as promising intervention targets. This work underscores the power of single-cell approaches to dissect drug responses and guide strategies to overcome resistance in malaria parasites.
Institutions: University of North Carolina at Chapel Hill, Brown University
Language: English
Topic: Malaria Research and Control
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
Awards: Artemisinin Resistance in Africa: its emergence and evolution in Rwanda, G4815247847, Variation in Resistance and Fitness to Artemisinins in African Malaria, Understanding Emerging artemisinin partner drug resistance in eastern Africa, Investigating the molecular mechanisms of Plasmodium vivax invasion in Duffy-negative hosts, Relapsing malaria in Africa: mechanisms for persistence amid falciparum decline, Mentoring in Translational Malaria Genomics
OpenAlex ID: W7171533044