In a recent online prepublication of Blood, the Journal of the American Society of Hematology, lead author Chris Moxon and co-authors from Malawi, UK and USA present their study outcome* implicating a novel pathway in the pathogenesis of cerebral malaria in African children. For the first time the article links clotting; inflammation and the sticking of malaria-infected red blood cells, called infected erythrocytes (IE), to small blood vessels - called ‘sequestration’- using samples from Malawian children, affected by cerebral malaria.
Cerebral malaria (CM) is a life-threatening complication of the disease where brain function is severely impaired and the patient becomes deeply unconscious. CM is a major cause of mortality in African children and the mechanisms underlying its development, namely how IE cause disease and why the brain is preferentially affected, remain unclear. Small areas of bleeding in the brain or microhaemorrhages in CM suggest a clotting disorder but whether this phenomenon is important in pathogenesis is debated.
The authors hypothesised that localised clotting in the brains of children with CM is caused by a decreased expression of specialised regulatory receptors called thrombomodulin (TM) and endothelial protein C receptor (EPCR), and that low baseline expression of these molecules in the brain make it particularly vulnerable.
Using a novel approach, they demonstrated loss of EPCR and TM at sites where IE accumulate. These data implicate disruption of important molecular switches in protective properties of blood vessels at vulnerable sites, particularly in the brain, and link coagulation and inflammation with IE sequestration in severe malaria. These findings may lead to the development of new treatments to improve CM outcome in children.
Author Chris Moxon is one of the first Wellcome Trust Clinical PhD fellows working with the Liverpool basedWellcome Trust Tropical Centre, a collaborative centre between LSTM and the University of Liverpool, and funded by the Wellcome Trust.
Prepublished online June 5, 2013