Conference Agenda

Resistance to the frontline antimalarial drug artemisinin is primarily mediated by mutations in the Plasmodium falciparum protein Kelch13 (K13), whose function has remained unclear. Parasites carrying mutant K13 ingest red blood cell haemoglobin more slowly. Because artemisinin is activated by haem released during parasite feeding, reduced haemoglobin uptake likely lowers intracellular levels of toxic artemisinin-derived species. How wild-type or mutant K13 contributes to this feeding process was unknown. Using multiple imaging approaches, we show that K13 localises to the collar that maintains the cytostome, a stable parasite invagination used for uptake of host cytosol. Three-dimensional electron microscopy reveals that mislocalised K13 abolishes formation of the electron-dense collar that stabilises the cytostomal neck and disrupts cytostome formation itself. Consistent with this, haemoglobin degradation products, including haem and haemozoin, are reduced when K13 is inactivated. Using expansion microscopy together with super-resolution and lattice light-sheet microscopy, we further show that new K13 collars form and segregate to daughter cells before division, but that this biogenesis is delayed in mutant parasites. These findings indicate that artemisinin resistance arises through defective cytostome formation, reduced endocytosis, and diminished drug activation in resistant parasites.