| Literature DB >> 25502316 |
Sachel Mok1, Elizabeth A Ashley2, Pedro E Ferreira1, Lei Zhu1, Zhaoting Lin1, Tomas Yeo1, Kesinee Chotivanich3, Mallika Imwong4, Sasithon Pukrittayakamee3, Mehul Dhorda5, Chea Nguon6, Pharath Lim7, Chanaki Amaratunga8, Seila Suon6, Tran Tinh Hien9, Ye Htut10, M Abul Faiz11, Marie A Onyamboko12, Mayfong Mayxay13, Paul N Newton14, Rupam Tripura15, Charles J Woodrow2, Olivo Miotto16, Dominic P Kwiatkowski17, François Nosten18, Nicholas P J Day2, Peter R Preiser1, Nicholas J White2, Arjen M Dondorp2, Rick M Fairhurst8, Zbynek Bozdech19.
Abstract
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.Entities:
Mesh：
Substances：
Year: 2014 PMID： 25502316 PMCID： PMC5642863 DOI： 10.1126/science.1260403
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728