Science (New York, N.Y.) · 2014
Drug resistance. Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance.
СтатьяResearch Support, N.I.H., IntramuralПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Mok Sachel, Ashley Elizabeth A, Ferreira Pedro E, Zhu Lei, Lin Zhaoting, Yeo Tomas, Chotivanich Kesinee, Imwong Mallika, Pukrittayakamee Sasithon, Dhorda Mehul, Nguon Chea, Lim Pharath, Amaratunga Chanaki, Suon Seila, Hien Tran Tinh, Htut Ye, Faiz M Abul, Onyamboko Marie A, Mayxay Mayfong, Newton Paul N, Tripura Rupam, Woodrow Charles J, Miotto Olivo, Kwiatkowski Dominic P, Nosten François, Day Nicholas P J, Preiser Peter R, White Nicholas J, Dondorp Arjen M, Fairhurst Rick M, Bozdech Zbynek
Аннотация
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. We analyzed the in vivo transcriptomes of 1043 P. falciparum isolates from patients with acute malaria and found 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, whereas their up-regulated 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.