How artemisinin resistance slows malaria parasite clearance?

Plasmodium falciparum unconventional resistance to artemisinin, defined by a slower parasite clearance with higher risk of relapse, is linked to mutations in the pfkelch13 gene. Specific molecular and cellular processes causing slower clearance remain unknown. We compared artemisinin-exposed red blood cells (RBCs) infected with either artemisinin-susceptible or artemisinin-resistant P. falciparum from patients and lab strains by membrane lipid content analyses, in vitro rheology and perfusion through human spleens. When exposed to artemisinin, resistant parasites showed reduced membrane lipid peroxidation, attenuated stiffness of their host RBC, and incomplete splenic retention, enabling their persistence in circulation. These results reveal the unexpected ability of artemisinin-resistant malaria parasites to preserve the deformability of their host RBCs as a mechanism of parasite survival after treatment. One-Sentence Summary: Artemisinin resistance is associated with reduced lipid peroxidation and enhanced parasite ability to escape retention in the spleen.