Abstract
SummaryAdherence of infected erythrocytes to vascular endothelium causes acute endothelial cell (EC) activation during Plasmodium falciparum infection. Consequently, proteins stored in Weibel-Palade (WP) bodies within EC are secreted into the plasma. Osteoprotegerin (OPG) binds to VWF and consequently is stored within WP bodies. Given the critical role of EC activation in the pathogenesis of severe malaria, we investigated plasma OPG levels in children with P. falciparum malaria. At presentation, plasma OPG levels were significantly elevated in children with cerebral malaria (CM) compared to healthy controls (means 16.0 vs 0.8 ng/ml; p<0.01). Importantly, OPG levels were also significantly higher in children with CM who had a fatal outcome, compared to children with CM who survived. Finally, in children with CM, plasma OPG levels correlated with other established prognostic indices (including plasma lactate levels and peripheral parasite density). To further investigate the relationship between severe malaria and OPG, we utilised a murine model of experimental CM in which C57BL/6J mice were infected with P. berghei ANKA. Interestingly, plasma OPG levels were increased 4.6 fold within 24 hours following P. berghei inoculation. This early marked elevation in OPG levels was observed before any objective clinical signs were apparent, and preceded the development of peripheral blood parasitaemia. As the mice became increasingly unwell, plasma OPG levels progressively increased. Collectively, these data suggest that OPG constitutes a novel biomarker with prognostic significance in patients with severe malaria. In addition, further studies are required to determine whether OPG plays a role in modulating malaria pathogenesis.
Highlights
Plasmodium falciparum malaria continues to be associated with significant morbidity and mortality [1, 2]
The molecular mechanisms underlying the pathogenesis of cerebral malaria (CM) remain poorly understood, previous studies have demonstrated a critical role for endothelial cell (EC) activation [4, 5]
We recently reported that platelet-decorated high-molecular-weight multimers (HMWM) von Willebrand factor (VWF) strings on the surface of activated EC can directly adhere to trophozoite-stage P. falciparum infected erythrocytes (IE) in a shear-based assay [20]
Summary
Plasmodium falciparum malaria continues to be associated with significant morbidity and mortality [1, 2]. A number of specific EC surface receptors, including CD36, endothelial protein C receptor (EPCR), E-selectin and intercellular adhesion molecule-1 (ICAM-1), have been shown to regulate the adhesion and sequestration of P. falciparum-infected erythrocytes (IE) within the microvasculature [6]. Quantitative expression of these different EC surface receptors on EC surfaces is modified by inflammatory cytokines, such as interleukin-1 and tumour necrosis factor [7]. A number of other EC proteins have been identified as WP body constituents These include VWF propeptide (VWFpp), P-selectin, factor VIII, angiopoietin-2, tissue-type plasminogen activator (tPA), interleukin-8, galectin-3 and osteoprote-
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