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Open Access Highly Accessed Research article

Artemisinin resistance in Plasmodium falciparum is associated with an altered temporal pattern of transcription

Sachel Mok1, Mallika Imwong23, Margaret J Mackinnon4, Joan Sim1, Ramya Ramadoss1, Poravuth Yi9, Mayfong Mayxay56, Kesinee Chotivanich2, Kek-Yee Liong1, Bruce Russell7, Duong Socheat9, Paul N Newton58, Nicholas PJ Day38, Nicholas J White38, Peter R Preiser1, François Nosten108, Arjen M Dondorp38* and Zbynek Bozdech1*

Author Affiliations

1 School of Biological Sciences, Nanyang Technological University, Singapore

2 Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Thailand

3 Mahidol-Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Thailand

4 KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya

5 Wellcome Trust-Mahosot Hospital-Oxford University Tropical Medicine Research Collaboration, Mahosot Hospital, Vientiane, Lao People's Democratic Republic

6 Faculty of Postgraduate Studies and Research, University of Health Sciences, Vientiane, Lao People's Democratic Republic

7 Singapore Immunology Network, Biopolis, Agency for Science Technology and Research (ASTAR), Singapore

8 Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, UK

9 The National Center for Parasitology, Entomology, and Malaria Control, Phnom Penh, Cambodia

10 Shoklo Malaria Research Unit, Mae Sot, Thailand

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BMC Genomics 2011, 12:391  doi:10.1186/1471-2164-12-391

Published: 3 August 2011

Abstract

Background

Artemisinin resistance in Plasmodium falciparum malaria has emerged in Western Cambodia. This is a major threat to global plans to control and eliminate malaria as the artemisinins are a key component of antimalarial treatment throughout the world. To identify key features associated with the delayed parasite clearance phenotype, we employed DNA microarrays to profile the physiological gene expression pattern of the resistant isolates.

Results

In the ring and trophozoite stages, we observed reduced expression of many basic metabolic and cellular pathways which suggests a slower growth and maturation of these parasites during the first half of the asexual intraerythrocytic developmental cycle (IDC). In the schizont stage, there is an increased expression of essentially all functionalities associated with protein metabolism which indicates the prolonged and thus increased capacity of protein synthesis during the second half of the resistant parasite IDC. This modulation of the P. falciparum intraerythrocytic transcriptome may result from differential expression of regulatory proteins such as transcription factors or chromatin remodeling associated proteins. In addition, there is a unique and uniform copy number variation pattern in the Cambodian parasites which may represent an underlying genetic background that contributes to the resistance phenotype.

Conclusions

The decreased metabolic activities in the ring stages are consistent with previous suggestions of higher resilience of the early developmental stages to artemisinin. Moreover, the increased capacity of protein synthesis and protein turnover in the schizont stage may contribute to artemisinin resistance by counteracting the protein damage caused by the oxidative stress and/or protein alkylation effect of this drug. This study reports the first global transcriptional survey of artemisinin resistant parasites and provides insight to the complexities of the molecular basis of pathogens with drug resistance phenotypes in vivo.

Keywords:
Plasmodium falciparum, in vivo artemisinin-resistance; field isolates; comparative genomics; comparative transcriptomics