The effects of dyslipidaemia and cholesterol modulation on erythrocyte susceptibility to malaria parasite infection

Symptoms of malaria disease are restricted to blood stages of infection. Disease commences when blood-stage parasites, called merozoites, invade human red blood cells. Whilst the process of invasion is traditionally seen as being entirely merozoite-driven, emerging data suggests red blood cell biophysical properties markedly influence parasite entry. Cholesterol is a major determinant of cell membrane biophysical properties. We therefore set out to assess whether cholesterol content in the red blood cell membrane affects susceptibility to merozoite invasion. Here we demonstrate that red blood cell bending modulus (a measure of deformability) is, as expected, markedly affected by cholesterol content and negatively correlated with merozoite invasion efficiency. To contextualise this observation to an in vivo setting, we used a mouse model of hypercholesterolemia and human clinical samples from patients with a range of serum cholesterol concentrations to test parasite susceptibility. Hypercholesterolaemia in both human and murine subjects had little effect merozoite invasion efficiency. On testing, red blood cell cholesterol content in both murine and human hypercholesterolaemia settings was, against expectations, unchanged. Therefore, serum cholesterol itself is unlikely to impact on susceptibility to merozoite ability to enter red blood cells directly. Our work, however, suggests that native polymorphisms affecting overall lipid metabolism, specifically red blood cell membrane composition, would be expected to affect parasite entry. Investigation of erythrocyte biophysical properties in endemic settings may, therefore, identify naturally protective lipid-related polymorphisms that confer protection through biophysical effects on the erythrocyte.