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

Abstract

Key Points• ECM is associated with an early marked increase in plasma VWF levels and accumulation of UL-VWF multimers.• Following P berghei infection, VWF 2/2 mice survive significantly longer compared with WT controls.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 plasma VWF levels. 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 2/2 C57BL/6J mice. Clinical ECM progression was delayed, and overall survival was significantly prolonged in VWF 2/2 mice compared with WT controls. Despite this protection against ECM, no significant differences in platelet counts or blood parasitemia levels were observed between VWF 2/2 and WT mice. Interestingly, however, the degree of ECMassociated enhanced blood-brain barrier permeability was significantly attenuated in VWF 2/2 mice compared with WT controls.Given the significant morbidity and mortality associated with CM, these novel data may have direct translational significance. (Blood. 2016;127(9):1192-1201) IntroductionPlasmodium falciparum malaria remains a major cause of morbidity and mortality among children in sub-Saharan Africa. [1][2][3] Although the biological mechanisms involved in the pathophysiology of severe P falciparum malaria remain poorly understood, previous studies have demonstrated that sequestration of P falciparum-infected erythrocytes (IEs) within the microvasculature of the brain is important in the development of cerebral malaria (CM). 4,5 This sequestration involves adhesion of IE to host vascular endothelial cell (EC) surfaces [6][7][8] and is mediated by a variety of specific EC adhesion molecules including CD36, intercellular adhesion molecule-1, and thrombospondin. 9 Moreover, recent studies have also demonstrated that the endothelial protein C receptor also plays an important role in modulating the sequestration of IE. 10 In addition to IE, sequestration of leukocytes and platelets within the cerebral microvasculature has also been reported in postmortem samples from CM patients. 11,12Von Willebrand factor (VWF)...

Exploring experimental cerebral malaria pathogenesis through the characterisation of host-derived plasma microparticle protein content

“…These functions are known to be important in the pathogenesis of both human and murine CM44344 and, in recent years, particular attention has been paid to the role of the endothelium in CM pathogenesis4546474849. The sequestration of different cell types at the brain microvasculature level - with predominant accumulation of pRBC in human CM and of leukocytes in ECM - is a typical trait of the syndrome4447.…”

Erg mediates downregulation of claudin‐5 in the brain endothelium of a murine experimental model of cerebral malaria

“…Following well‐established procedures , we generated an ECM model by infecting C57BL/6 mice with PbA. On the blood smears obtained from days 3 and 6 p.i.…”

“…Claudin-5 expression is decreased in brain endothelium of a murine model of ECM Following well-established procedures [28,29], we generated an ECM model by infecting C57BL/6 mice with PbA. On the blood smears obtained from days 3 and 6 p.i.…”

Unravelling the roles of innate lymphoid cells in cerebral malaria pathogenesis

“…As the homoeostasis protein von Willebrand factor (VWF) and its multimers are increased in plasma of patients with malaria, the role of VWF was investigated in Pb A‐infected C57BL/6 mice, which also exhibit increased plasma VWF levels. In VWF‐deficient mice, Pb A‐induced ECM development was delayed, BBB permeability reduced, survival increased, while platelet counts and parasitaemia were not affected, as compared with wild‐type controls. Thus, the data suggest that VWF associated with CM participates in ECM, independent of platelet functions.…”