New Findings Shed Light on Cause of Cerebral Malaria That Kills 1 Million African Children Each Year
Posted on: 05 August 2009
A novel pathway that may contribute to the high mortality associated with severe malaria in African children has been identified by researchers from an international collaborative study led by Dr James O’ Donnell, Director of the Haemostasis Research Group at Trinity College Dublin and St James’s Hospital, Dublin. The research, which was recently published in the prestigious publication PLoS Pathogen, was funded by the Wellcome Trust and Science Foundation Ireland.
Severe Plasmodium falciparum malaria is responsible for an estimated 1 million deaths each year in sub-Saharan African children. In spite of this significant mortality, the mechanisms underlying the clinical development of severe malaria remain poorly understood. However, studies have shown that red blood cells (erythrocytes) infected with malaria parasites can adhere to the inner lining endothelium of small blood vessels. In this study, the researchers wanted to investigate the significance of this interaction between the infected erythrocytes and the blood vessel wall.
Over a one-year period, they studied children under six years presenting to the Komfe Anokye hospital in Kumasi, Ghana with severe P. falciparum malaria. In blood samples from these children, the researchers found that plasma levels of a specific adhesive protein called Von Willebrand Factor (VWF) were markedly increased. This VWF is synthesised within endothelial cells, and is secreted in response to activation. As a result of its multimeric structure, this VWF plays a critical role in tethering circulating blood cells to the vascular wall at sites of injury. In order to prevent excessive blood clot formation, VWF activity in the blood is normally tightly regulated by a VWF-specific cleaving enzyme called ADAMTS13. In the Ghanaian children presenting with severe malaria, the plasma levels of this important ADAMTS13 enzyme were also found to be significantly reduced.
Thus, severe P. falciparum malaria infection causes disruption of the endothelium, resulting in the release of large amounts of VWF into the blood. Moreover, this VWF protein cannot be inactivated due to a concurrent decrease in plasma ADAMTS13 enzyme levels. Further studies will be required to define the role played by the abnormal, highly adhesive VWF in mediating the critical small vessel obstruction associated with severe malaria.
Commenting on the significance of the findings, Dr James O’Donnell said: “This research sheds new light on the mechanisms underlying the interaction between the malaria parasite and its human host, and are not only of scientific interest, but may also open future new therapeutic opportunities for these children.”