Artemisinin resistance mutations inPfcoroninimpede hemoglobin uptake

Abstract

AbstractArtemisinin (ART) combination therapies have been critical in reducing malaria morbidity and mortality, but these important drugs are threatened by growing resistance associated with mutations inPfcoroninandPfkelch13. Here, we describe the mechanism ofPfcoronin-mediated ART resistance.PfCoronin interacts withPfActin and localizes to membranes of the parasite periphery, the digestive vacuole (DV), and a putative pre-DV compartment (PPDC)—all structures involved in the trafficking of hemoglobin from the RBC for degradation in the DV.Pfcoroninmutations alterPfActin homeostasis and impair the development and morphology of the PPDC. Ultimately, these changes are associated with decreased uptake of red blood cell cytosolic contents by ring-stagePlasmodium falciparum. Previous work has identified decreased hemoglobin uptake as the mechanism ofPfkelch13-mediated ART resistance. This work demonstrates thatPfCoronin appears to act via a parallel pathway. For bothPfkelch13-mediated andPfcoronin-mediated ART resistance, we hypothesize that the decreased hemoglobin uptake in ring stage parasites results in less heme-based activation of the artemisinin endoperoxide ring and reduced cytocidal activity. This study deepens our understanding of ART resistance, as well as hemoglobin uptake and development of the DV in early-stage parasites.