Abstract
Malaria remains one of the world’s most important infectious diseases and is responsible for enormous mortality and morbidity. Resistance to antimalarial drugs is a challenging problem in malaria control. Clinical malaria is associated with the proliferation and development of Plasmodium parasites in human erythrocytes. Especially, the development into the mature forms (trophozoite and schizont) of Plasmodium falciparum (P. falciparum) causes severe malaria symptoms due to a distinctive property, sequestration which is not shared by any other human malaria. Ca2+ is well known to be a highly versatile intracellular messenger that regulates many different cellular processes. Cytosolic Ca2+ increases evoked by extracellular stimuli are often observed in the form of oscillating Ca2+ spikes (Ca2+ oscillation) in eukaryotic cells. However, in lower eukaryotic and plant cells the physiological roles and the molecular mechanisms of Ca2+ oscillation are poorly understood. Here, we showed the observation of the inositol 1,4,5-trisphospate (IP3)-dependent spontaneous Ca2+ oscillation in P. falciparum without any exogenous extracellular stimulation by using live cell fluorescence Ca2+ imaging. Intraerythrocytic P. falciparum exhibited stage-specific Ca2+ oscillations in ring form and trophozoite stages which were blocked by IP3 receptor inhibitor, 2-aminoethyl diphenylborinate (2-APB). Analyses of parasitaemia and parasite size and electron micrograph of 2-APB-treated P. falciparum revealed that 2-APB severely obstructed the intraerythrocytic maturation, resulting in cell death of the parasites. Furthermore, we confirmed the similar lethal effect of 2-APB on the chloroquine-resistant strain of P. falciparum. To our best knowledge, we for the first time showed the existence of the spontaneous Ca2+ oscillation in Plasmodium species and clearly demonstrated that IP3-dependent spontaneous Ca2+ oscillation in P. falciparum is critical for the development of the blood stage of the parasites. Our results provide a novel concept that IP3/Ca2+ signaling pathway in the intraerythrocytic malaria parasites is a promising target for antimalarial drug development.
Highlights
Malaria continues to be a worldwide public health problem causing significant morbidity and mortality and its resistance to existing antimalarial drugs is a growing problem [1]
Ca2+ imaging of parasites was performed in culture chambers at 37uC in an atmosphere of 5% O2 and 5% CO2, conditions identical to those in conventional in vitro parasite culture
Ca2+ depletion by pre-treatment with 100 nM concanamycin A (CMA) had no effect on Ca2+ oscillations in early ring forms (ERf, left) and early trophozoites (ET, right) (Fig. S4E). In these two stages the digestive food vacuole, which is known to be a Ca2+ pool sensitive to both thapsigargin and a vacuolar-type H+-ATPase inhibitor, bafilomycin A1 [19], is not formed. These results indicate that spontaneous IP3-induced Ca2+ release from a thapsigarginsensitive Ca2+ store, endoplasmic reticulum (ER) occurred in early ring forms and early trophozoites during intraerythrocytic P. falciparum development
Summary
Malaria continues to be a worldwide public health problem causing significant morbidity and mortality and its resistance to existing antimalarial drugs is a growing problem [1]. 2-APB Blocks P. falciparum Development The effects of 2-APB on intraerythrocytic development were investigated using synchronized parasite cultures in the ring form stage, with initial parasitaemia of approximately 1%.
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