Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance

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Science  11 Dec 2014:
DOI: 10.1126/science.1260403

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Artemisinin resistance in Plasmodium falciparum threatens global efforts to control and eliminate malaria. Polymorphisms in the kelch domain-carrying protein K13 are associated with artemisinin resistance, but the underlying molecular mechanisms are unknown. Here we analyze the in-vivo transcriptomes of 1,043 P. falciparum isolates from patients with acute malaria, and show that artemisinin resistance is associated with increased expression of unfolded protein response (UPR) pathways involving the major PROSC and TRiC chaperone complexes. Artemisinin resistant parasites also exhibit decelerated progression through the first part of the asexual intraerythrocytic development cycle. These findings suggest that artemisinin resistant parasites remain in a state of decelerated development at the young ring stage while their upregulated UPR pathways mitigate protein damage caused by artemisinin. The expression profiles of UPR-related genes also associate with the geographical origin of parasite isolates, further suggesting their role in emerging artemisinin resistance in the Greater Mekong Subregion.

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