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Abstract
Platelet adhesion to the brain microvasculature has been associated with cerebral malaria (CM) in humans, suggesting that platelets play a role in the pathogenesis of this syndrome. In vitro co-cultures have shown that platelets can act as a bridge between Plasmodium falciparum-infected red blood cells (pRBC) and human brain microvascular endothelial cells (HBEC) and potentiate HBEC apoptosis. Using cDNA microarray technology, we analyzed transcriptional changes of HBEC in response to platelets in the presence or the absence of tumor necrosis factor (TNF) and pRBC, which have been reported to alter gene expression in endothelial cells. Using a rigorous statistical approach with multiple test corrections, we showed a significant effect of platelets on gene expression in HBEC. We also detected a strong effect of TNF, whereas there was no transcriptional change induced specifically by pRBC. Nevertheless, a global ANOVA and a two-way ANOVA suggested that pRBC acted in interaction with platelets and TNF to alter gene expression in HBEC. The expression of selected genes was validated by RT-qPCR. The analysis of gene functional annotation indicated that platelets induce the expression of genes involved in inflammation and apoptosis, such as genes involved in chemokine-, TREM1-, cytokine-, IL10-, TGFβ-, death-receptor-, and apoptosis-signaling. Overall, our results support the hypothesis that platelets play a pathogenic role in CM.
Highlights
Malaria remains a major problem of public health in tropical developing countries worldwide
We have investigated the respective effects of tumor necrosis factor (TNF), PL and Plasmodium falciparum-infected red blood cells (pRBC) on human brain endothelial cells by profiling gene expression from in vitro co-cultures
Our results confirm that endothelial cells activated by TNF contribute to endothelial cell apoptosis and leukocyte chemotaxis and activation
Summary
Malaria remains a major problem of public health in tropical developing countries worldwide. Close to 230 million people (World Health Organization) are infected annually with Plasmodium falciparum. About 1–2% out of clinical attacks of malaria are complicated by severe manifestations leading to death. The major syndromes of severe malaria are severe anaemia, severe respiratory distress, and cerebral malaria (CM) [1]. Severe malaria predominantly affects children under 5 years of age, non-immune adults, and pregnant women. The outcome of infection depends on numerous factors, including host and parasite genetics, host age, rates of infection, and host immune status
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