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

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; Franҫois Nosten; Nicholas P.J. Day; Peter R. Preiser; Nicholas J. White; Arjen M. Dondorp; Rick M. Fairhurst; Zbynek Bozdech

doi:10.1126/science.1260403

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

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. NewtonRupam Tripura, Charles J. Woodrow, Olivo Miotto, Dominic P. Kwiatkowski, Franҫois Nosten, Nicholas P.J. Day, Peter R. Preiser, Nicholas J. White, Arjen M. Dondorp, Rick M. Fairhurst, Zbynek Bozdech^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

325 Citations (Scopus)

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.

Original language	English
Pages (from-to)	431-435
Number of pages	5
Journal	Science
Volume	347
Issue number	6220
DOIs	https://doi.org/10.1126/science.1260403
Publication status	Published - Jan 23 2015
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2015, American Association for the Advancement of Science. All rights reserved.

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General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Mok, S., Ashley, E. A., Ferreira, P. E., Zhu, L., Lin, Z., Yeo, T., Chotivanich, K., Imwong, M., Pukrittayakamee, S., Dhorda, M., Nguon, C., Lim, P., Amaratunga, C., Suon, S., Hien, T. T., Htut, Y., Faiz, M. A., Onyamboko, M. A., Mayxay, M., ... Bozdech, Z. (2015). Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance. Science, 347(6220), 431-435. https://doi.org/10.1126/science.1260403

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title = "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.",

author = "Sachel Mok and Ashley, {Elizabeth A.} and Ferreira, {Pedro E.} and Lei Zhu and Zhaoting Lin and Tomas Yeo and Kesinee Chotivanich and Mallika Imwong and Sasithon Pukrittayakamee and Mehul Dhorda and Chea Nguon and Pharath Lim and Chanaki Amaratunga and Seila Suon and Hien, {Tran Tinh} and Ye Htut and Faiz, {M. Abul} and Onyamboko, {Marie A.} and Mayfong Mayxay and Newton, {Paul N.} and Rupam Tripura and Woodrow, {Charles J.} and Olivo Miotto and Kwiatkowski, {Dominic P.} and Franҫois Nosten and Day, {Nicholas P.J.} and Preiser, {Peter R.} and White, {Nicholas J.} and Dondorp, {Arjen M.} and Fairhurst, {Rick M.} and Zbynek Bozdech",

year = "2015",

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Mok, S, Ashley, EA, Ferreira, PE, Zhu, L, Lin, Z, Yeo, T, Chotivanich, K, Imwong, M, Pukrittayakamee, S, Dhorda, M, Nguon, C, Lim, P, Amaratunga, C, Suon, S, Hien, TT, Htut, Y, Faiz, MA, Onyamboko, MA, Mayxay, M, Newton, PN, Tripura, R, Woodrow, CJ, Miotto, O, Kwiatkowski, DP, Nosten, F, Day, NPJ, Preiser, PR, White, NJ, Dondorp, AM, Fairhurst, RM & Bozdech, Z 2015, 'Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance', Science, vol. 347, no. 6220, pp. 431-435. https://doi.org/10.1126/science.1260403

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T1 - Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance

AU - Mok, Sachel

AU - Ashley, Elizabeth A.

AU - Ferreira, Pedro E.

AU - Zhu, Lei

AU - Lin, Zhaoting

AU - Yeo, Tomas

AU - Chotivanich, Kesinee

AU - Imwong, Mallika

AU - Pukrittayakamee, Sasithon

AU - Dhorda, Mehul

AU - Nguon, Chea

AU - Lim, Pharath

AU - Amaratunga, Chanaki

AU - Suon, Seila

AU - Hien, Tran Tinh

AU - Htut, Ye

AU - Faiz, M. Abul

AU - Onyamboko, Marie A.

AU - Mayxay, Mayfong

AU - Newton, Paul N.

AU - Tripura, Rupam

AU - Woodrow, Charles J.

AU - Miotto, Olivo

AU - Kwiatkowski, Dominic P.

AU - Nosten, Franҫois

AU - Day, Nicholas P.J.

AU - Preiser, Peter R.

AU - White, Nicholas J.

AU - Dondorp, Arjen M.

AU - Fairhurst, Rick M.

AU - Bozdech, Zbynek

PY - 2015/1/23

Y1 - 2015/1/23

N2 - 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.

AB - 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.

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SN - 0036-8075

VL - 347

SP - 431

EP - 435

JO - Science

JF - Science

IS - 6220

ER -

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

Abstract

Bibliographical note

ASJC Scopus Subject Areas

UN SDGs

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