Project description:In order to further our understanding of the metabolic network of the malaria parasite, Plasmodium falciparum, we carried out a concurrent transcriptomic and metabolomic study of the parasite's intraerythrocytic developmental cycle. These microarray data were generated to compare the expression levels of metabolic enzymes to the concentrations of their associated metabolites over the 48-hour life cycle.
Project description:Lactic acidosis, driven by hyperlactatemia, is a hallmark of severe Plasmodium falciparum malaria, yet its impact on parasitic life cycle and gene expression remains unclear. In mammalian cells, lactate influences transcription through histone lactylation, a novel post-translational modification. In this study, we demonstrate that P. falciparum undergoes lactate-derived lysine lactylation on nuclear proteins, including histones, histone variants, and AP2 transcription factors, with lactylation levels dynamically varying in response to physiological lactate ranges. Through CUT&RUN profiling, we show that elevated lactate enhances chromatin occupancy of lactylated proteins at promoters of genes involved in virulence and cytoadherence. Correspondingly, transcriptomic analyses demonstrated a suppression of these genes in response to elevated lactate, a pattern also evident in clinical isolates from severe malaria patients. Functionally, we demonstrate that high lactate reduces the binding ability of infected erythrocytes to CD36 receptor. Together, our findings reveal protein lactylation as a metabolite-responsive epigenetic mechanism in P. falciparum, linking host metabolic state to transcriptional reprogramming with direct implications for parasite virulence and disease pathogenesis.
Project description:Investigations on the fundamental of malaria parasite biology, such as invasion, growth cycle, metabolism and cell signalling have uncovered a number of potential antimalarial drug targets, including choline kinase, a key enzyme involved in the synthesis of phosphatidylcholine, an important component in parasite membrane compartment. The effect on gene expression of Plasmodium falciparum K1 strain following 72 hours exposure to 2 μM (IC50 concentration) of the choline kinase inhibitor, hexadecyltrimethylammonium bromide (HDTAB) was evaluated by DNA microarray analysis. Genes important in P. falciparum intra-erythrocytic life cycle, such as invasion, cytoadherance and growth were among those affected by at least 2-fold changes in their expression levels compared with non HDTAB-treated control.
Project description:The human malaria parasite Plasmodium falciparum employs intricate post-transcriptional regulatory mechanisms in different stages of its life cycle. Despite the importance of post-transcriptional regulation, key elements of these processes, namely RNA binding proteins (RBPs), are poorly characterized. In this study, the RNA binding properties of P. falciparum proteins were characterized including two putative members of the Bruno/CELF family of RBPs (PfCELF1 and PfCELF2), dihydrofolate reductase-thymidylate synthase (PfDHFR-TS), and adenosine deaminase (PfAda).The mRNA targets of these P. falciparum proteins were investigated by ribonomics using DNA microarrays.