Molecular bases of the transduction of the signal of the cell cycle of malaria parasites

Abstract

Malaria is one of the major causes of morbidity and mortality in the third world. Plasmodia, the causal agent of malaria, are unicellular parasites that in humans spend most of their life within intact cells. After initial infection from a mosquito bite, the Plasmodia first invade and differentiate in hepatocytes, and this is followed by a repetitive cycle of proliferation and reinvasion in red blood cells. Within the latter cells, Plasmodia multiply and mature inside a membrane-bound vacuole that fully surrounds the parasites. Mature merozoite-stage parasites are released by RBC Iysis and go on to invade other RBCs. One of the most striking features of malarial infections is the periodicity of the fevers they engender. These occur at multiples of 24 hours. The cyclic fever that characterizes malarial infections is the outward manifestation of the parasite development. As a consequence the rupture of erythrocytes and the parasite invasion into new cells is a highly synchronized event, which helps the parasite evading the immune system of its host. Interestingly, this synchronicity is lost in vitro. Until recently title was known about the mechanisms by which parasite synchronicity is established and maintained. We have recently reported that the host hormone melatonin, produced by the pineal gland, which is responsible for the transduction of cyclic environmental variation and therefore organize temporally the internal biological events in mammals, is the molecule responsible for synchronizing Plasmodium development in vivo and in vitro. Activation of phospholipids C, production of InsP3 and induction of calcium release in its intracellular stores was then proposed. Several cell physiological and pharmacological studies in Plasmodium point to an involvement of calcium signaling in the maturation process of the parasite. The present project will investigate the calcium-based mechanisms for regulating signaling processes of Plasmodium cell cycle in human, rodent and lizard parasites. Its knowledge will represent a major breakthrough and therefore might open new avenues for therapy. (AU)