title: Artemisinin resistance in Plasmodium falciparum is associated with an altered temporal pattern of transcription.
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.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Sachel
authors.initials: S
authors.lastname: Mok
authors.forename: Mallika
authors.initials: M
authors.lastname: Imwong
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Mackinnon
authors.forename: Joan
authors.initials: J
authors.lastname: Sim
authors.forename: Ramya
authors.initials: R
authors.lastname: Ramadoss
authors.forename: Poravuth
authors.initials: P
authors.lastname: Yi
authors.forename: Mayfong
authors.initials: M
authors.lastname: Mayxay
authors.forename: Kesinee
authors.initials: K
authors.lastname: Chotivanich
authors.forename: Kek-Yee
authors.initials: KY
authors.lastname: Liong
authors.forename: Bruce
authors.initials: B
authors.lastname: Russell
authors.forename: Duong
authors.initials: D
authors.lastname: Socheat
authors.forename: Paul N
authors.initials: PN
authors.lastname: Newton
authors.forename: Nicholas P J
authors.initials: NP
authors.lastname: Day
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.forename: Peter R
authors.initials: PR
authors.lastname: Preiser
authors.forename: François
authors.initials: F
authors.lastname: Nosten
authors.forename: Arjen M
authors.initials: AM
authors.lastname: Dondorp
authors.forename: Zbynek
authors.initials: Z
authors.lastname: Bozdech
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D056915:DNA Copy Number Variations / Q000187:drug effects / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics*; D020869:Gene Expression Profiling; D023281:Genomics; D005838:Genotype; D006801:Humans; D010963:Plasmodium falciparum / Q000166:cytology / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D015800:Protozoan Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects*; D053058:Trophozoites / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D015800:Protozoan Proteins; C031327:artemisinin