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

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.

Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia

“…Mutations in this pathway could result in cell cycle arrest, as was observed in a PRR knockout model in yeast (24). Such down-regulation of the cell cycle is consistent with reduced DNA synthesis and other metabolic functions observed in the ring and trophozoite stages of parasites showing delayed clearance following artemisinin treatment (25).…”

Assessment of the Induction of Dormant Ring Stages in Plasmodium falciparum Parasites by Artemisone and Artemisone Entrapped in Pheroid Vesicles In Vitro

“…A plausible explanation for recrudescence is drug-induced quiescence or dormancy that protects ring-stage parasites against artemisinin exposure (9,10). The artemisinin-treated ring stages of P. falciparum thereby enter a temporary growth arrest (11,12), wherein they survive drug treatment, resuming normal growth once drug pressure is removed (13)(14)(15).…”

The Use of Some of the Information Criterion in Determining the Best Model for Forecasting of Thalassemia Cases Depending on Iraqi Patient Data Using ARIMA Model

“…This is done by observing the graph of the data or autocorrelation and the partial autocorrelation functions [2]. It notes, through a graph of the time series, that there are high rates of Thalassemia as compared with previous years (Figure 1).…”

“…Another classification of Thalassemia is according to the site of the defect in the protein molecule of the red blood cells, according to which: α-and β-Thalassemia, β-Thalassemia is a common hereditary disorder caused by mutations in one or more of the β-globin gene loci that result in reduced β-globin production [2]. Recently, more than 200 different mutations have been detected affecting a variety of levels of β-globin gene expression causing β-Thalassemia.…”