Additionally, cytoadherenceindependent mechanisms, such as metabolic acidosis due to PRBC maturation or the release of parasite factors such as merozoite proteins, histones and plasma uric acid also contribute to endothelial damage. Finally, the induction of EC apoptosis by PRBC, platelets and neutrophils would severely disrupt endothelial integrity. Finally, it was shown that the potential of P. falciparum to cause human lung EC apoptosis in vitro varies with the isolate, and that this might in turn be linked to the expression of a subset of parasite genes named ”Plasmodium apoptosis–linked Bortezomib pathogenicity factors”. Recent studies have confirmed that the parasite-induced apoptosis described in vitro also occurs in the brain, lung and kidney of fatal malaria cases While different mechanisms for the EC damage have been studied, its role in the gamut of the clinical manifestations remains poorly understood. In this study, we wished to ascertain whether the apoptotic potential of PRBC is the same for ECs of different origin, and whether this varies for distinct P. falciparum isolates. To this end, we used HLEC and the human brain microvascular EC line, hCMEC/D3, that is used for pathogenic and drug transport studies, to assess the ability of three parasite strains derived from clinical isolates to induce apoptosis in these brain or lung ECs. The HBEC line hCMEC/D3 was a gift from Prof. P. O. Couraud. This cell line shows a stable normal karyotype, maintained contact-inhibited monolayers in tissue culture, exhibited robust proliferation in response to endothelial growth factors, and formed capillary tubes in matrix but no colonies in soft agar. The hCMEC/D3 cells expresse telomerase and grow indefinitely without phenotypic dedifferentiation. These cells expressed chemokine receptors, up-regulated adhesion molecules in response to inflammatory cytokines, and demonstrated blood-brain barrier characteristics, including tight junction proteins and the capacity to actively exclude drugs. HBECs were cultured in a brain culture 
medium composed of EBM-2 basal medium supplemented with growth medium Bullet kit 2 as previously described. Clinically, the course of the P. falciparum infection varies from the chronic asymptomatic to the rapidly fatal, and the gamut of symptoms extends from non-specific mild fevers to clearly delineated severe organ-specific syndromes. Whereas it is not possible to predict the clinical evolution at the level of the individual, the risk for a given population to develop a particular Torin 1 pathology is generally known. It is accepted that the hosts’ genetic background, their level of acquired immunity, the exposure to which they are subjected, and other factors such as nutritional and general health status influence the expression of clinical severity. In P. falciparum infections, the extreme levels of sequestration amplify the interactions between the parasite and the endothelium and exacerbate inflammatory responses and endothelial activation. Thus, for infections with this parasite species alterations in the function and in the integrity of the endothelial barrier are likely to play a key role in the development of clinical severity. In here we focused on the induction of EC apoptosis by interactions with the PRBC, a phenomenon that is most likely to impair endothelial integrity.