Abstract
Severe malaria is primarily caused by Plasmodium falciparum parasites during their asexual reproduction cycle within red blood cells. One of the least understood stages in this cycle is the brief preinvasion period during which merozoite-red cell contacts lead to apical alignment of the merozoite in readiness for penetration, a stage of major relevance in the control of invasion efficiency. Red blood cell deformations associated with this process were suggested to be active plasma membrane responses mediated by transients of elevated intracellular calcium. Few studies have addressed this hypothesis because of technical challenges, and the results remained inconclusive. Here, Fluo-4 was used as a fluorescent calcium indicator with optimized protocols to investigate the distribution of the dye in red blood cell populations used as P. falciparum invasion targets in egress-invasion assays. Preinvasion dynamics was observed simultaneously under bright-field and fluorescence microscopy by recording egress-invasion events. All the egress-invasion sequences showed red blood cell deformations of varied intensities during the preinvasion period and the echinocytic changes that follow during invasion. Intraerythrocytic calcium signals were absent throughout this interval in over half the records and totally absent during the preinvasion period, regardless of deformation strength. When present, calcium signals were of a punctate modality, initiated within merozoites already poised for invasion. These results argue against a role of elevated intracellular calcium during the preinvasion stage. We suggest an alternative mechanism of merozoite-induced preinvasion deformations based on passive red cell responses to transient agonist-receptor interactions associated with the formation of adhesive coat filaments.
Highlights
Most cases of severe malaria in humans are caused by the malaria parasite Plasmodium falciparum (Pf), one of the five malaria parasite species infecting humans
In studies of Pf growth using cultures sustained with red blood cells (RBCs) of different densities to reflect different hydration states, it was found that the invasion efficiency decreased progressively with the increase in RBC density [3]
Effects of FA and pyruvate on P. falciparum invasion and growth. The aim of these experiments was to establish whether Pf invasion could be affected by the FA released during the incorporation of AM-compounds into RBCs, and, if so, whether pyruvate could prevent these effects [29]
Summary
Most cases of severe malaria in humans are caused by the malaria parasite Plasmodium falciparum (Pf), one of the five malaria parasite species infecting humans. It is the asexual reproduction cycle of the parasite within human red blood cells (RBCs), initiated by merozoite invasion, that is responsible for the symptoms in malaria disease. Because disease severity is associated with high parasitemia, the density effect contributes protection by preventing the develop-. Ment of high parasitemia in all inherited RBC abnormalities associated with the presence of dense RBC subpopulations [3]. The search for clues to the possible mechanisms of this density effect focused attention on the events taking place between the instant a merozoite makes first contact with an RBC and the time when it becomes apically aligned, ready for invasion—the preinvasion stage
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