A novel role for von Willebrand factor in the pathogenesis of experimental cerebral malaria

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Abstract

Plasmodium falciparum malaria infection is associated with an early marked increase in plasma von Willebrand factor (VWF) levels, together with a pathological accumulation of hyperreactive ultra-large VWF (UL-VWF) multimers. Given the established critical role of platelets in malaria pathogenesis, these increases in plasma VWF raise the intriguing possibility that VWF may play a direct role in modulating malaria pathogenesis. To address this hypothesis, we used an established murine model of experimental cerebral malaria (ECM), in which wild-type (WT) C57BL/6J mice were infected with Plasmodium berghei ANKA. In keeping with findings in children with P falciparum malaria, acute endothelial cell activation was an early and consistent feature in the murine model of cerebral malaria (CM), resulting in significantly increased plasmaVWFlevels. Despite the fact that murine plasma ADAMTS13 levels were not significantly reduced, pathological UL-VWF multimers were also observed in murine plasma following P berghei infection. To determine whether VWF plays a role in modulating the pathogenesis of CM in vivo, we further investigated P berghei infection in VWF-/- C57BL/6J mice. Clinical ECM progression was delayed, and overall survival was significantly prolonged in VWF-/- mice compared withWTcontrols. Despite this protection against ECM, no significant differences in platelet counts or blood parasitemia levels were observed between VWF-/- and WT mice. Interestingly, however, the degree of ECMassociated enhanced blood-brain barrier permeability was significantly attenuated in VWF-/- mice compared with WT controls. Given the significant morbidity and mortality associated with CM, these novel data may have direct translational significance.

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O’regan, N., Gegenbauer, K., O’sullivan, J. M., Maleki, S., Brophy, T. M., Dalton, N., … O’Donnell, J. S. (2016). A novel role for von Willebrand factor in the pathogenesis of experimental cerebral malaria. Blood, 127(9), 1192–1201. https://doi.org/10.1182/blood-2015-07-654921

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