Abstract
BackgroundArtemisinin 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.ResultsIn 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.ConclusionsThe 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.
Highlights
Artemisinin resistance in Plasmodium falciparum malaria has emerged in Western Cambodia
We show that the P. falciparum parasites with slow clearance after artemisinin treatment exhibit reduced expression levels of generic metabolic or cellular (e.g. DNA replication) pathways in the ring and trophozoite stages but strong increased expression of essentially all functionalities associated with protein synthesis, folding and trafficking in the schizont stages
Gene expression associated with artemisinin resistance The main purpose of these studies was to characterize the transcriptional profile associated with artemisinin resistance in field isolates of P. falciparum [15]
Summary
Artemisinin resistance in Plasmodium falciparum malaria has emerged in Western Cambodia. The core components of ACTs artemisinin and its derivatives, provide an important alternative to quinoline and antifolate-based compounds Resistance to these older compounds that emerged on the Thai-Cambodian border and subsequently spread across the world has severely compromised their use and contributed to a dramatic rise in malaria morbidity prior to introduction of the ACTs in the late 1990’s [4,5,6,7]. Learning from past mistakes, much effort is being invested in proper management of ACTs in order to sustain their efficacy and prevent the spread of resistance [1] In spite of these efforts, there have been sporadic reports of artemisinin resistance in-vivo and in-vitro for many years (from Yunnan Province, Southwest China [8], Vietnam [9] and French Guiana [10]). It has yet to be established whether artemisinin resistance has spread westward, the possibility of the spread of resistant parasites through Asia to Africa would be disastrous
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