Plasmodium falciparum--infected erythrocyte adhesion induces caspase activation and apoptosis in human endothelial cells.
During Plasmodium falciparum infection leading to cerebral malaria, cytokine production and cytoadherence of parasitized erythrocytes (PRBCs) to postcapillary venules are involved. We demonstrate that PRBC adhesion induces apoptosis in human endothelial cells (HLECs). PRBC adhesion modulated HLEC gene expression in tumor necrosis factor-alpha superfamily genes (Fas, Fas L, and DR-6) and apoptosis-related genes (Bad, Bax, caspase-3,SARP 2, DFF45/ICAD, IFN-gamma receptor 2, Bcl-w, Bik, and iNOS). Apoptosis was confirmed by (1) morphological modifications by electron microscopy, (2) annexin V binding, (3) DNA degradation, by measuring intracytoplasmic nucleosomes, and (4) caspase activity. The apoptotic stimulus was physical contact between HLECs and PRBCs and not parasite-secreted molecules. In addition, it was found that cytoplasmic (caspase 8) and mitochondrial (caspase 9) pathways were involved in this process. These data not only describe the direct apoptotic effect of PRBC adhesion on endothelial cells but also provide new useful tools that allow an evaluation of potential pharmaceuticals.
Pino
Paco
P
INSERM U511, Immunobiologie Cellulaire et Moléculaire des Infections Parasitaires, Centre Hospitalier-Universitaire Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris, France.
Vouldoukis
Ioannis
I
Kolb
Jean Pierre
JP
Mahmoudi
Nassira
N
Desportes-Livage
Isabelle
I
Bricaire
François
F
Danis
Martin
M
Dugas
Bernard
B
Mazier
Dominique
D
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D004351:Drug Resistance; D004727:Endothelium / Q000201:enzymology* / Q000473:pathology*; D004789:Enzyme Activation; D004903:Erythrocyte Aggregation; D004912:Erythrocytes / Q000469:parasitology* / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D008168:Lung / Q000166:cytology; D016778:Malaria, Falciparum / Q000097:blood; D010963:Plasmodium falciparum / Q000502:physiology*
D000962:Antimalarials; D020169:Caspases