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

被引：298

作者：

Mok, Sachel ^{[1
]}

Ashley, Elizabeth A. ^{[2
,3
]}

Ferreira, Pedro E. ^{[1
]}

Zhu, Lei ^{[1
]}

Lin, Zhaoting ^{[1
]}

Yeo, Tomas ^{[1
]}

Chotivanich, Kesinee ^{[4
]}

Imwong, Mallika ^{[5
]}

Pukrittayakamee, Sasithon ^{[4
]}

Dhorda, Mehul ^{[3
,6
,7
]}

Nguon, Chea ^{[8
]}

Lim, Pharath ^{[8
,9
]}

Amaratunga, Chanaki ^{[9
]}

Suon, Seila ^{[8
]}

Tran Tinh Hien ^{[10
]}

Htut, Ye ^{[11
]}

Faiz, M. Abul ^{[12
]}

Onyamboko, Marie A. ^{[13
]}

Mayxay, Mayfong ^{[14
,15
]}

Newton, Paul N. ^{[2
,3
,14
]}

Tripura, Rupam ^{[2
]}

Woodrow, Charles J. ^{[2
,3
]}

Miotto, Olivo ^{[2
,16
,17
]}

Kwiatkowski, Dominic P. ^{[16
,17
]}

Nosten, Francois ^{[3
,18
]}

Day, Nicholas P. J. ^{[2
,3
]}

Preiser, Peter R. ^{[1
]}

White, Nicholas J. ^{[2
,3
]}

Dondorp, Arjen M. ^{[2
,3
]}

Fairhurst, Rick M. ^{[9
]}

Bozdech, Zbynek ^{[1
]}

机构：

[1] Nanyang Technol Univ, Sch Biol Sci, Singapore 639798, Singapore

[2] Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Bangkok 10700, Thailand

[3] Univ Oxford, Nuffield Dept Med, Ctr Trop Med & Global Hlth, Oxford, England

[4] Mahidol Univ, Fac Trop Med, Dept Clin Trop Med, Bangkok 10700, Thailand

[5] Mahidol Univ, Fac Trop Med, Dept Mol Trop Med & Genet, Bangkok, Thailand

[6] Mahidol Univ, Asia Reg Ctr, WorldWide Antimalarial Resistance Network WWARN, Bangkok 10700, Thailand

[7] Univ Maryland, Sch Med, WorldWide Antimalarial Resistance Network, Baltimore, MD 21201 USA

[8] Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia

[9] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA

[10] Hosp Trop Dis, OUCRU, Ho Chi Minh City, Vietnam

[11] Dept Med Res, Lower Myanmar, Yangon, Myanmar

[12] Malaria Res Grp & Dev Care Fdn, Dhaka, Bangladesh

[13] Kinshasa Sch Publ Hlth, Kinshasa, DEM REP CONGO

[14] Lao Oxford Mahosot Hosp, Wellcome Trust Res Unit, Mahosot Hosp, Viangchan, Laos

[15] Univ Hlth Sci, Fac Postgrad Studies, Viangchan, Laos

[16] Univ Oxford, Ctr Genom & Global Hlth, MRC, Oxford, England

[17] Wellcome Trust Sanger Inst, Cambridge, England

[18] Mahidol Univ, Fac Trop Med, Shoklo Malaria Res Unit, Mahidol Oxford Trop Med Res Unit, Mae Sot, Thailand

来源：

SCIENCE | 2015年 / 347卷 / 6220期

基金：

英国惠康基金;

关键词：

PLASMODIUM-FALCIPARUM MALARIA; DIHYDROARTEMISININ-PIPERAQUINE; WESTERN CAMBODIA; CLEARANCE RATE; PROVINCE; PROTEIN; VIVAX;

D O I：

10.1126/science.1260403

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：431 / 435

页数：5

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