Drug Resistance. Population Transcriptomics of Human Malaria Parasites Reveals the Mechanism of Artemisinin Resistance

Overview

Journal Science

Specialty Science

Date 2014 Dec 16

PMID 25502316

Citations 216

Authors

Sachel Mok

Elizabeth A Ashley

Pedro E Ferreira

Lei Zhu

Zhaoting Lin

Tomas Yeo

Kesinee Chotivanich

Mallika Imwong

Sasithon Pukrittayakamee

Mehul Dhorda

Chea Nguon

Pharath Lim

Chanaki Amaratunga

Seila Suon

Tran Tinh Hien

Ye Htut

M Abul Faiz

Marie A Onyamboko

Mayfong Mayxay

Paul N Newton

Rupam Tripura

Charles J Woodrow

Olivo Miotto

Dominic P Kwiatkowski

Francois Nosten

Nicholas P J Day

Peter R Preiser

Nicholas J White

Arjen M Dondorp

Rick M Fairhurst

Zbynek Bozdech

Affiliations

Soon will be listed here.

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.

Citing Articles

Endoplasmic Reticulum Stress: Implications in Diseases.

Walter N, Gorki V, Bhardwaj R, Punnakkal P Protein J. 2025; .

PMID: 40082380 DOI: 10.1007/s10930-025-10264-x.

Monitoring molecular markers associated with antimalarial drug resistance in south-east Senegal from 2021 to 2023.

Wade A, Sene S, Caspar E, Diallo F, Platon L, Thiebaut L J Antimicrob Chemother. 2025; 80(3):828-839.

PMID: 39846779 PMC: 11879165. DOI: 10.1093/jac/dkaf006.

transcription factor AP2-06B is mutated at high frequency in Southeast Asia but does not associate with drug resistance.

Shi Q, Wang C, Yang W, Ma X, Tang J, Zhang J Front Cell Infect Microbiol. 2025; 14():1521152.

PMID: 39835275 PMC: 11744005. DOI: 10.3389/fcimb.2024.1521152.

First, Do No Harm: Addressing AI's Challenges With Out-of-Distribution Data in Medicine.

Weng C, Lin W, Dong S, Liu Q, Zhang H Clin Transl Sci. 2025; 18(1):e70132.

PMID: 39821661 PMC: 11739455. DOI: 10.1111/cts.70132.

Metabolic changes that allow artemisinin-resistant parasites to tolerate oxidative stress.

Bonive-Boscan A, Acosta H, Rojas A Front Parasitol. 2025; 3():1461641.

PMID: 39817177 PMC: 11731681. DOI: 10.3389/fpara.2024.1461641.

References

Mok S, Imwong M, Mackinnon M, Sim J, Ramadoss R, Yi P . Artemisinin resistance in Plasmodium falciparum is associated with an altered temporal pattern of transcription. BMC Genomics. 2011; 12:391. PMC: 3163569. DOI: 10.1186/1471-2164-12-391. View

Oakley M, Gerald N, McCutchan T, Aravind L, Kumar S . Clinical and molecular aspects of malaria fever. Trends Parasitol. 2011; 27(10):442-9. DOI: 10.1016/j.pt.2011.06.004. View

Phyo A, Nkhoma S, Stepniewska K, Ashley E, Nair S, McGready R . Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study. Lancet. 2012; 379(9830):1960-6. PMC: 3525980. DOI: 10.1016/S0140-6736(12)60484-X. View

Hartl F, Hayer-Hartl M . Molecular chaperones in the cytosol: from nascent chain to folded protein. Science. 2002; 295(5561):1852-8. DOI: 10.1126/science.1068408. View

Khattak A, Venkatesan M, Khatoon L, Ouattara A, Kenefic L, Nadeem M . Prevalence and patterns of antifolate and chloroquine drug resistance markers in Plasmodium vivax across Pakistan. Malar J. 2013; 12:310. PMC: 3766695. DOI: 10.1186/1475-2875-12-310. View

Tongaonkar P, Selsted M . SDF2L1, a component of the endoplasmic reticulum chaperone complex, differentially interacts with {alpha}-, {beta}-, and {theta}-defensin propeptides. J Biol Chem. 2008; 284(9):5602-9. PMC: 2645818. DOI: 10.1074/jbc.M806664200. View

Ariey F, Witkowski B, Amaratunga C, Beghain J, Langlois A, Khim N . A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature. 2013; 505(7481):50-5. PMC: 5007947. DOI: 10.1038/nature12876. View

White N . The parasite clearance curve. Malar J. 2011; 10:278. PMC: 3195204. DOI: 10.1186/1475-2875-10-278. View

Klonis N, Crespo-Ortiz M, Bottova I, Abu-Bakar N, Kenny S, Rosenthal P . Artemisinin activity against Plasmodium falciparum requires hemoglobin uptake and digestion. Proc Natl Acad Sci U S A. 2011; 108(28):11405-10. PMC: 3136263. DOI: 10.1073/pnas.1104063108. View

10.

Takala-Harrison S, Clark T, Jacob C, Cummings M, Miotto O, Dondorp A . Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia. Proc Natl Acad Sci U S A. 2012; 110(1):240-5. PMC: 3538248. DOI: 10.1073/pnas.1211205110. View

11.

Saunders D, Vanachayangkul P, Lon C . Dihydroartemisinin-piperaquine failure in Cambodia. N Engl J Med. 2014; 371(5):484-5. DOI: 10.1056/NEJMc1403007. View

12.

Bozdech Z, Llinas M, Pulliam B, Wong E, Zhu J, DeRisi J . The transcriptome of the intraerythrocytic developmental cycle of Plasmodium falciparum. PLoS Biol. 2003; 1(1):E5. PMC: 176545. DOI: 10.1371/journal.pbio.0000005. View

13.

Dondorp A, Fairhurst R, Slutsker L, MacArthur J, Breman J, Guerin P . The threat of artemisinin-resistant malaria. N Engl J Med. 2011; 365(12):1073-5. PMC: 3733336. DOI: 10.1056/NEJMp1108322. View

14.

Witkowski B, Amaratunga C, Khim N, Sreng S, Chim P, Kim S . Novel phenotypic assays for the detection of artemisinin-resistant Plasmodium falciparum malaria in Cambodia: in-vitro and ex-vivo drug-response studies. Lancet Infect Dis. 2013; 13(12):1043-9. PMC: 5015432. DOI: 10.1016/S1473-3099(13)70252-4. View

15.

Ellgaard L, Helenius A . Quality control in the endoplasmic reticulum. Nat Rev Mol Cell Biol. 2003; 4(3):181-91. DOI: 10.1038/nrm1052. View

16.

Miotto O, Almagro-Garcia J, Manske M, MacInnis B, Campino S, Rockett K . Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia. Nat Genet. 2013; 45(6):648-55. PMC: 3807790. DOI: 10.1038/ng.2624. View

17.

Leang R, Barrette A, Mey Bouth D, Menard D, Abdur R, Duong S . Efficacy of dihydroartemisinin-piperaquine for treatment of uncomplicated Plasmodium falciparum and Plasmodium vivax in Cambodia, 2008 to 2010. Antimicrob Agents Chemother. 2012; 57(2):818-26. PMC: 3553743. DOI: 10.1128/AAC.00686-12. View

18.

Hien T, Thuy-Nhien N, Phu N, Boni M, Thanh N, Nha-Ca N . In vivo susceptibility of Plasmodium falciparum to artesunate in Binh Phuoc Province, Vietnam. Malar J. 2012; 11:355. PMC: 3504531. DOI: 10.1186/1475-2875-11-355. View

19.

Cheeseman I, Miller B, Nair S, Nkhoma S, Tan A, Tan J . A major genome region underlying artemisinin resistance in malaria. Science. 2012; 336(6077):79-82. PMC: 3355473. DOI: 10.1126/science.1215966. View

20.

Amaratunga C, Sreng S, Suon S, Phelps E, Stepniewska K, Lim P . Artemisinin-resistant Plasmodium falciparum in Pursat province, western Cambodia: a parasite clearance rate study. Lancet Infect Dis. 2012; 12(11):851-8. PMC: 3786328. DOI: 10.1016/S1473-3099(12)70181-0. View