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

O'Regan, Niamh, Gegenbauer, Kristina, O'Sullivan, Jamie M, Maleki, Sanaz, Brophy, Teresa M, Dalton, Niall, Chion, Alain, Fallon, Padraic G, Grau, Georges E, Budde, Ulrich, Smith, Owen P, Craig, Alister ORCID: https://orcid.org/0000-0003-0914-6164, Preston, Roger J S and O'Donnell, James S (2015) 'A novel role for von Willebrand factor in the pathogenesis of experimental cerebral malaria'. Blood, Vol 127, Issue 9, pp. 1192-1201.

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Abstract

Plasmodium falciparum malaria infection is associated with an early marked increase in plasma VWF levels, together with a pathological accumulation of hyper-reactive 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 utilized 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 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(-/-) C57BL/6J mice. Clinical ECM progression was delayed and overall survival was significantly prolonged in VWF(-/-) mice compared to wild type controls. Despite this protection against ECM, no significant differences in platelet counts, or blood parasitaemia levels, were observed between VWF(-/-) and WT mice. Interestingly however, the degree of ECM-associated enhanced blood brain barrier permeability was significantly attenuated in VWF(-/-) mice compared to WT controls. Given the significant morbidity and mortality associated with CM, these novel data may have direct translational significance.

Item Type: Article
Subjects: QX Parasitology > Protozoa > QX 135 Plasmodia
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
WH Hemic and Lymphatic Systems > Hematologic Diseases. Immunologic Factors. Blood Banks > WH 310 Mechanism of blood coagulation. Hemostatis
Faculty: Department: Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI): https://doi.org/10.1182/blood-2015-07-654921
Depositing User: Mary Creegan
Date Deposited: 02 Dec 2015 15:31
Last Modified: 17 Jul 2019 14:14
URI: https://archive.lstmed.ac.uk/id/eprint/5409

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