Mechanisms of artemisinin resistance in Plasmodium falciparum malaria

Artemisinin-based combination therapies (ACTs) have substantially reduced worldwide malaria burden and deaths. But malaria parasites have become resistant to artemisinins. Prior studies suggested two different molecular pathways of artemisinin-resistance. Here we unify recent findings into a single model, where elevation of a lipid, phosphatidylinositol-3- phosphate (PI3P) results in vesicle expansion that increases the engagement with the unfolded protein response (UPR). Vesicle expansion (rather than increasing individual genetic determinants of the UPR) efficiently induces artemisinin resistance likely by promoting ‘proteostasis’ (protein translation coupled to proper protein folding and vesicular remodeling) to mitigate artemisinin-induced proteopathy (death from global abnormal protein-toxicity). Vesicular amplification engages the host red cell, suggesting that artemisinin resistant malaria may also persist by taking advantage of host niches and escaping the immune response.