Brain lesions of cerebral malaria (CM) are characterised by a sequestration of Plasmodium falciparum-parasitised red blood cells (PRBC),
leucocytes and platelets within brain microvessels, by an excessive release of pro-inflammatory cytokines as well as by disruption of the blood–brain
barrier (BBB). We evaluated the possibility that PRBC and platelets interact and induce functional alterations in brain endothelium. Using an in vitro
model of endothelial lesion, we showed that platelets can act as bridges between PRBC and endothelial cells (EC) allowing the binding of PRBC to
endothelium devoid of cytoadherence receptors. Furthermore, platelets potentiated the cytotoxicity of PRBC for brain EC by inducing an alteration
of the integrity of their monolayer and increasing their apoptosis. These findings provide insights into the mechanisms by which platelets can be
deleterious to the brain endothelium during CM. Another aspect of inflammatory and infectious diseases is that they often lead to activation of
vascular and blood cells. Such activation results in an enhanced vesiculation, i.e. the release of circulating microparticles (MP). We thus explored
plasma levels of endothelial MP in Malawian children with malaria. Plasma MP numbers were markedly increased on admission only in patients
with severe malaria complicated with coma. Using the experimental mouse model of CM, we evaluated the pathogenic implications of MP using
genetically deficient mice in which the capacity to vesiculate is impaired. Such mice, lacking the ABCA-1 gene, upon infection by Plasmodium
berghei ANKA, showed complete resistance to CM. When purified from infected susceptible animals, MP were able to reduce normal plasma
clotting time and to significantly enhance tumour necrosis factor release from naı¨ve macrophages. Altogether these data provide a novel insight into
the pathogenic mechanisms leading to the neurological syndrome. The finding that ABCA-1 gene deletion confers complete protection against
cerebral pathology, linked to an impaired MP production, provides new potential targets for therapeutic amelioration of severe malaria.