Artemisinin resistance mutations in Pfcoronin impede hemoglobin uptake

Ullah, I.; Farringer, M. A.; Burkhard, A. Y.; Hathaway, E.; Willett, B. C.; Khushu, M.; Shin, S. H.; Sharma, A. I.; Shao, K. L.; Martin, M. C.; Dvorin, J. D.; Hartl, D. L.; Volkman, S. K.; Bopp, S.; Absalon, S.; Wirth, D. F.

doi:10.1101/2023.12.22.572193

bioRxiv · 10.1101/2023.12.22.572193

Artemisinin resistance mutations in Pfcoronin impede hemoglobin uptake

Ullah, I.·Farringer, M. A.·Burkhard, A. Y.·Hathaway, E.·Willett, B. C.·Khushu, M.·Shin, S. H.·Sharma, A. I.·Shao, K. L.·Martin, M. C.·Dvorin, J. D.·Hartl, D. L.·Volkman, S. K.·Bopp, S.·Absalon, S.·Wirth, D. F.

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Abstract

Artemisinin (ART) combination therapies have been critical in reducing malaria morbidity and mortality, but these important drugs are threatened by growing resistance associated with mutations in Pfcoronin and Pfkelch13. Here, we describe the mechanism of Pfcoronin-mediated ART resistance. PfCoronin interacts with PfActin and localizes to the parasite plasma membrane (PPM), the digestive vacuole (DV) membrane, and membrane of a newly identified preDV compartment--all structures involved in the trafficking of hemoglobin from the RBC for degradation in the DV. Pfcoronin mutations alter PfActin homeostasis and impair the development and morphology of the preDV. Ultimately, these changes are associated with decreased uptake of red blood cell cytosolic contents by ring-stage Plasmodium falciparum. Previous work has identified decreased hemoglobin uptake as the mechanism of Pfkelch13-mediated ART resistance. This work demonstrates that PfCoronin appears to act via a parallel pathway. For both Pfkelch13-mediated and Pfcoronin-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.

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Ullah, I., Farringer, M. A., Burkhard, A. Y., Hathaway, E., Willett, B. C., Khushu, M., Shin, S. H., Sharma, A. I., Shao, K. L., Martin, M. C., Dvorin, J. D., Hartl, D. L., Volkman, S. K., Bopp, S., Absalon, S., Wirth, D. F.. 2023-12-22. Artemisinin resistance mutations in Pfcoronin impede hemoglobin uptake. https://doi.org/10.1101/2023.12.22.572193

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