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

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.

SUBMITTER: Mok S

PROVIDER: S-EPMC5642863 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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

Mok Sachel S Ashley Elizabeth A EA Ferreira Pedro E PE Zhu Lei L Lin Zhaoting Z Yeo Tomas T Chotivanich Kesinee K Imwong Mallika M Pukrittayakamee Sasithon S Dhorda Mehul M Nguon Chea C Lim Pharath P Amaratunga Chanaki C Suon Seila S Hien Tran Tinh TT Htut Ye Y Faiz M Abul MA Onyamboko Marie A MA Mayxay Mayfong M Newton Paul N PN Tripura Rupam R Woodrow Charles J CJ Miotto Olivo O Kwiatkowski Dominic P DP Nosten François F Day Nicholas P J NP Preiser Peter R PR White Nicholas J NJ Dondorp Arjen M AM Fairhurst Rick M RM Bozdech Zbynek Z

Science (New York, N.Y.) 20141211 6220

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 ma ...[more]

PMID: 25502316

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Project description:In the malaria parasite Plasmodium falciparum, synthesis of isoprenoids from glycolytic intermediates is essential for survival. The antimalarial fosmidomycin (FSM) inhibits isoprenoid synthesis. In P. falciparum, we identified a loss-of-function mutation in HAD2 (P. falciparum 3D7_1226300 [PF3D7_1226300]) as necessary for FSM resistance. Enzymatic characterization revealed that HAD2, a member of the haloacid dehalogenase-like hydrolase (HAD) superfamily, is a phosphatase. Harnessing a growth defect in resistant parasites, we selected for suppression of HAD2-mediated FSM resistance and uncovered hypomorphic suppressor mutations in the locus encoding the glycolytic enzyme phosphofructokinase 9 (PFK9). Metabolic profiling demonstrated that FSM resistance is achieved via increased steady-state levels of methylerythritol phosphate (MEP) pathway and glycolytic intermediates and confirmed reduced PFK9 function in the suppressed strains. We identified HAD2 as a novel regulator of malaria parasite metabolism and drug sensitivity and uncovered PFK9 as a novel site of genetic metabolic plasticity in the parasite. Our report informs the biological functions of an evolutionarily conserved family of metabolic regulators and reveals a previously undescribed strategy by which malaria parasites adapt to cellular metabolic dysregulation.IMPORTANCE Unique and essential aspects of parasite metabolism are excellent targets for development of new antimalarials. An improved understanding of parasite metabolism and drug resistance mechanisms is urgently needed. The antibiotic fosmidomycin targets the synthesis of essential isoprenoid compounds from glucose and is a candidate for antimalarial development. Our report identifies a novel mechanism of drug resistance and further describes a family of metabolic regulators in the parasite. Using a novel forward genetic approach, we also uncovered mutations that suppress drug resistance in the glycolytic enzyme PFK9. Thus, we identify an unexpected genetic mechanism of adaptation to metabolic insult that influences parasite fitness and tolerance of antimalarials.

Dataset Information

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

Publications

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

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