James O’Donnell

The global morbidity and mortality caused by malaria infection are staggering. Between 300 million and 500 million cases of clinical malaria occur each year, resulting in more than 500,000 deaths. Unfortunately, the majority of these deaths (~80%) occur in African children under age five. Consequently, malaria constitutes one of the leading causes of death in young children worldwide. Indeed the United Nations estimates that malaria is responsible for the death of a child in sub-Saharan Africa every 30 seconds. Cerebral malaria (CM) is a life-threatening complication of malaria infection. Young children with CM typically present to hospital with severe headache and drowsiness. Unfortunately, as the malaria infection worsens, the children rapidly progress to develop confusion, decreased consciousness and unrousable coma. Although effective anti-malarial drugs have been developed, in up to 20% of children CM still proves fatal. Furthermore, 20% of the children who survive CM are left with long term complications including learning difficulties and memory impairment. In spite of the significant mortality and morbidity associated with CM, the effects if the malaria parasite in causing disease remain poorly understood. This lack of understanding has impeded the development of new and much needed treatment options for children who develop CM. To further investigate the biology underlying CM in children, we have established a Malaria Research Consortium. This Consortium includes collaborators in Dublin, the Liverpool School of Tropical Medicine, University of Sydney and Blantyre in Malawi. In previous studies, this Consortium has identified a novel role for a specific blood clotting protein called von Willebrand factor (VWF) in malaria. In the blood, this clotting protein is able to bind to red cells infected with malaria parasites. In this study, the Consortium will investigate further how VWF influences malaria progression. Ultimately, we hope that insights into how VWF is important in children with malaria infection may provide new treatment options for children with CM.

Although sickle cell disease (SCD) is associated with significant paediatric morbidity and mortality, the pathophysiology underlying micro-vascular occlusion in SCD remains poorly understood. However, a critical step in this vascular occlusion involves adhesion of sickle erythrocytes to vascular endothelial cells (EC). Interestingly, emerging data suggests a novel role for the plasma glycoprotein von Willebrand factor (VWF) in modulating the EC adhesion of sickle erythrocytes. The objective of the current study is to define the molecular mechanisms through which VWF, and in particular ultra-large multimeric forms of VWF, influence SCD pathogenesis in children. Through this application, we propose to develop a new Sickle Vascular Ireland Consortium (SiVIC). SiVIC will unite the clinical resource and deep phenotypic data already collected in the Irish Sickle Centre in OLCHC with the vascular research expertise in the Irish Centre for Vascular Biology (ICVB) network in order to investigate the biology involved in SCD vascular occlusion. In this first SiVIC study, we will specifically investigate the hypothesis that dysfunction of the VWF-ADAMTS13 axis in children with SCD leads to the pathological UL-VWF multimer accumulation and thereby promotes microvascular occlusion. Sickle cell disease (SCD) is responsible for major paediatric morbidity and mortality. Globally, more than 1000 children with SCD are born every day. Unfortunately, in resource-poor countries, half of these children die before reaching five years of age and less than 10% actually survive to adulthood. Even in developed countries, SCD continues to be associated with significant paediatric morbidity. For example, 10% of US children with SCD develop symptomatic strokes that commonly result in learning problems and lifelong disabilities. Consequently, there is an urgent unmet need to develop novel adjunctive therapies to improve clinical outcomes in children with SCD.