Abstract
BackgroundMalaria disease commences when blood-stage parasites, called merozoites, invade human erythrocytes. Whilst the process of invasion is traditionally seen as being entirely merozoite-driven, emerging data suggests erythrocyte biophysical properties markedly influence invasion. Cholesterol is a major determinant of cell membrane biophysical properties demanding its interrogation as a potential mediator of resistance to merozoite invasion of the erythrocyte.MethodsBiophysical measurements of erythrocyte deformability by flicker spectroscopy were used to assess changes in erythrocyte bending modulus on forced integration of cholesterol and how these artificial changes affect invasion by human Plasmodium falciparum merozoites. To validate these observations in a natural context, either murine Plasmodium berghei or human Plasmodium falciparum merozoites were tested for their ability to invade erythrocytes from a hypercholesterolaemic mouse model or human clinical erythrocyte samples deriving from patients with a range of serum cholesterol concentrations, respectively.ResultsErythrocyte bending modulus (a measure of deformability) was shown to be markedly affected by artificial modulation of cholesterol content and negatively correlated with merozoite invasion efficiency. In an in vitro infection context, however, erythrocytes taken from hypercholesterolaemic mice or from human clinical samples with varying serum cholesterol levels showed little difference in their susceptibility to merozoite invasion. Explaining this, membrane cholesterol levels in both mouse and human hypercholesterolaemia erythrocytes were subsequently found to be no different from matched normal serum controls.ConclusionsBased on these observations, serum cholesterol does not appear to impact on erythrocyte susceptibility to merozoite entry. Indeed, no relationship between serum cholesterol and cholesterol content of the erythrocyte is apparent. This work, nonetheless, suggests that native polymorphisms which do affect membrane lipid composition would be expected to affect parasite entry. This supports investigation of erythrocyte biophysical properties in endemic settings, which may yet identify naturally protective lipid-related polymorphisms.
Highlights
Malaria disease commences when blood-stage parasites, called merozoites, invade human erythrocytes
A significant change in plasma lipid levels is medically described as dyslipidaemia, a term used to categorize a number of conditions, including hypercholesterolaemia, which is associated with an increase in plasma cholesterol levels
Artificial incorporation of membrane cholesterol inhibits Plasmodium falciparum merozoite invasion Based on previous findings, demonstrating that a reduction in the erythrocyte bending modulus resulted in an increased merozoite invasion efficiency [10], it was hypothesized that stiffening the erythrocyte membrane by increasing cholesterol content would result in a lower merozoite invasion efficiency
Summary
Malaria disease commences when blood-stage parasites, called merozoites, invade human erythrocytes. Cholesterol is a key constituent of human cells and plays a key role in modulating membrane properties, influencing both membrane fluidity [1] and stiffness [2, 3]. The effect on these cellular properties is mediated by cholesterol’s flat rigid structure which is defined by the planar tetracyclic ring shape of the molecule. A number of studies have found differences in how treatment of elevated plasma cholesterol or clinical conditions with dyslipidaemia is associated with differences in erythrocyte membrane cholesterol levels [4,5,6]
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