Cerebral malaria (CM) is a major cause of death in young children in sub-Saharan Africa. Although the pathogenesis of this condition remains poorly understood, Plasmodium falciparum infection results in adhesion of infected erythrocytes (IE) to microvascular endothelium, and acute endothelial cell (EC) activation. Recent studies have shown that plasma VWF:Ag and VWF propeptide levels are markedly elevated in children with severe falciparum malaria. Moreover elevated VWF:Ag levels inversely correlate with clinical outcomes. In addition, circulating ultra-large VWF multimers have also been observed in children with severe malaria. Importantly, platelet-decorated UL-VWF strings have been shown to recruit trophozoite-stage falciparum-IE to EC surfaces in shear-based assays. Collectively, these emerging data suggest that VWF may play a novel role in the pathogenesis of CM. To further investigate this hypothesis, we utilized an established murine model of experimental CM which involves wild type (WT) C57BL/6J mice infected with Plasmodium berghei ANKA. In brief, WT C57Bl/6J mice were inoculated with 2x106P. berghei ANKA via I.P. injection. These mice typically developed CM and died within 6-8 days. In keeping with findings in children with falciparum malaria, acute EC activation was also an early and consistent feature in the murine model of CM. Mean plasma VWF:Ag levels were significantly elevated from Day+3 in infected mice compared to controls (Day +3 1.8 fold increase; Day +5 2.5 fold increase; p<0.01). In addition, plasma angiopoietin-2 and osteoprotegerin levels were also both significantly elevated from Day +3 and Day +5 respectively in mice infected with P. berghei. Interestingly, despite the fact that murine plasma ADAMTS13 activity levels were not significantly reduced, pathological ultra-large VWF multimers (UL-VWF) were also observed in murine plasma from Day +3 following P. berghei inoculation. Cumulatively these findings suggest that early marked elevation in VWF:Ag levels, and the appearance of pathological UL-VWF multimers in the plasma, represent hallmarks of both human and murine severe malaria infection. To determine whether VWF plays a direct role in modulating the pathogenesis of CM in vivo, we further investigated P. berghei infection in VWF-/- C57BL/6J mice. Importantly, although there was no difference in blood parasitaemia levels, overall survival was significantly prolonged in VWF-/- mice compared to wild type mice (6 versus 7.25 days; p=0.0106). Moreover, a significant delay in malaria clinical progression in the VWF-/- mice was also observed using a previously validated clinical scoring algorithm for experimental cerebral malaria. (Amante et al, Am J Path 2007). Recent studies have demonstrated that platelets may play a direct role in modulating malaria parasite killing. Consequently, to investigate potential mechanisms through which VWF-/- mice are protected against experimental CM, daily platelet counts were determined in WT and VWF-/- mice following infection. In keeping with observations in human patients infected with falciparum malaria, significant thrombocytopenia was also a consistent feature in the murine model. For example, by Day +4 following inoculation of WT mice mean platelet count had fallen by 71.6 ± 26 %. Interestingly however, significant thrombocytopenia was also observed in VWF-/- mice infected with P. berghei (84.2 ± 9 %). Despite the significant differences in clinical progression and overall survival no significant differences in platelet counts were observed between VWF-/- and WT mice at any time point. These findings suggest that VWF-/-mice are protected against CM through a platelet-independent mechanism. In conclusion, we demonstrate that early and consistent EC activation is a feature of the murine model of experimental CM similar to previous findings of children infected with P. falciparum. In addition, our findings show that marked elevation of VWF:Ag, and the appearance of pathological UL-VWF multimers in the plasma, both represent hallmarks of human and murine severe malaria infection. Finally, we report that VWF-/- mice exhibit significantly prolonged survival against CM, and that this effect is mediated through a platelet-independent mechanism. Given the significant morbidity and mortality associated with CM, these novel data have direct translational significance. Disclosures No relevant conflicts of interest to declare.
Denis Parsons Burkitt, surgeon and research scientist, is a household name in the medical profession. Denis received his BA in 1933 and graduated as a physician in 1935 from Trinity College, Dublin. After serving as a surgeon in the Royal Army Medicine Corps during World War II, he worked as a surgeon and lecturer in Africa. It was in Africa that he developed exceptional observational and analytical skills, which led him to identify and formally develop a successful treatment for a childhood cancer that is now called Burkitt Lymphoma. The influence of Christianity in his life was huge. Throughout his life he remained extremely modest, attributing much of what he had achieved to the work of others. Denis's contributions to haemato-oncology remain salient today, and his discoveries continue to generate new research. Throughout his career he received some of the highest scientific honours from many different countries across the globe.
This paper argues for redefining evaluation criteria for faculty working in new media research and makes specific recommendations for promotion and tenure committees in U.S. universities.
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