Trends in Parasitology
OpinionIs invasion efficiency in malaria controlled by pre-invasion events?
Section snippets
The ‘density effect’ and the search for possible mechanisms
Recent observations [1] demonstrated that the efficiency of Plasmodium falciparum merozoites to invade red blood cells (RBCs) decreases inversely with RBC density. The presence of abnormally dense RBCs in the circulation, by reducing the fraction of RBCs available for invasion, would prevent the development of high parasitaemias, and hence reduce the incidence of cerebral malaria, which is the form of the disease that causes mortality [2]. This represents a protection strategy additional to any
Examining the invasion process
The video recording by Dvorak et al. [7], with fixed focus at ×1000 magnification, shows the invasion events in real time in a variety of cells. In one instance, a merozoite, reportedly attached to the glass, is seen in edge contact with a typical biconcave-shaped RBC. While the merozoite remained steady, the RBC is seen to move spontaneously towards and away from the merozoite with its membrane enfolding substantial extents of the merozoite surface in each approach, reminiscent of phagocytic
Analysis of the merozoite invasion sequence
The observations just described identify two distinct dynamic morphological stages during merozoite invasion. In the first stage, the pre-invasion stage, merozoite attachment triggers immediate and rapid shape changes of the targeted RBC. These enfold the merozoite, radiating from the point of merozoite attachment, and vary continuously in shape and direction. After a variable time of ∼10–30 s, all dynamic motion ceases, and the RBC returns to its relaxed biconcave shape while the second stage,
Function of the pre-invasion stage
Because penetration starts immediately after the first wave of deformation, it follows that the merozoite must be apically aligned at the end of the pre-invasion stage. Hence, the processes taking place during the pre-invasion stage represent the actual mechanism of apical reorientation, a function also foreseen by Hermentin [15] and by Cowman and Crabb [16]. The duration of the pre-invasion stage would be determined by the time it takes to position the merozoite in apical contact with the RBC,
A working hypothesis on the pre-invasion stage
Of the various mechanisms that could possibly explain the pre-invasion events we wish to consider one which might have become amenable to experimental scrutiny with current methodologies. Invasion requires the presence of Ca2+ in the medium 19, 20, 21, 22. It is prevented in intact RBCs loaded non-disruptively with Ca2+ chelators and suspended in Ca2+-containing media, indicating that external Ca2+ is required for elevating the intracellular free calcium concentration ([Ca2+]i) 23, 24.
Significance and relevance of the working hypothesis
The pre-invasion process tests the ability of RBCs to provide an adequate motile response to merozoite contacts. A poor motile response reduces the probability of a successful apical alignment and hence the frequency of invasion. Thus invasion efficiency will be reduced in any condition in which abnormalities of RBC hydration, haemoglobin, cytoskeleton, membrane lipid composition, metabolism, or membrane transport generate a deficient motile response during the pre-invasion stage 43, 44, 45.
Acknowledgements
We thank the Wellcome Trust and the Biotechnology and Biological Sciences Research Council for funds. We are grateful to Hagai Ginsburg and to the anonymous Reviewers for helpful comments and criticisms.
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Importance of Erythrocyte Deformability for the Alignment of Malaria Parasite upon Invasion
2019, Biophysical JournalEvidence against a Role of Elevated Intracellular Ca<sup>2+</sup> during Plasmodium falciparum Preinvasion
2018, Biophysical JournalCitation Excerpt :The results in Fig. 7 showed no preferential correlation with presence (green) or absence (red) of Ca2+ signals at any of the deformation intensities scored. We investigated the hypothesized role of elevated [Ca2+]i on the deformation responses that merozoite contacts elicit in RBCs during the preinvasion period (5). We sought to overcome methodological uncertainties from earlier studies concerning the ATP depletion status of the RBCs targeted for invasion, the possibility of false negatives from low-Fluo-4 containing RBCs, and the possibility of brief events being missed during the relatively large gaps in early time-lapse video recordings (10).
Disorders of erythrocyte hydration
2017, BloodCitation Excerpt :Erythrocyte aging has been associated with alterations in membrane permeability for calcium.57 Localized membrane deformation has been associated with increased calcium in the initial steps of malaria invasion,58 a process recently linked to PIEZO1 phosphorylation.59 It has been suggested that PIEZO plays a role in erythrocyte volume regulation,60 with PIEZO1-mutant HX erythrocytes gradually becoming dehydrated during their repeated cycles of travel through the microcirculation, associated with changes in oxygenation/deoxygenation.61
The Molecular Basis of Erythrocyte Invasion by Malaria Parasites
2017, Cell Host and MicrobeThe Rheopathobiology of Plasmodium vivax and Other Important Primate Malaria Parasites
2017, Trends in ParasitologyCitation Excerpt :The next important change to host RBC rheology occurs following merozoite invasion (∼30 s post attachment) when the IRBC begins to undergo echinocytosis [1,7]. This process appears to be due to a rapid change in the osmotic potential of the RBC, because calcium ions enter the RBC cytosol from the extracellular environment (as the merozoite reseals the RBC membrane behind its entry point) and the newly formed parasitophorous vacuole (which is relatively permeable to calcium ions) [10,11]. For the 5–10 min that these IRBCs remain echinocytic, they are undoubtedly rigid and, therefore, would be easily trapped in the microvasculature or the splenic sinusoids.
Piezo proteins: Regulators of mechanosensation and other cellular processes
2014, Journal of Biological Chemistry