Tue10 Apr05:15pm(15 mins)
Stream 2 - Llandinam A6
It remains unclear why a child develops CM at a particular time, as the vast majority of P. falciparum infections do not lead to CM. We investigated if the pathogenesis of CM is driven by parasite variants that preferentially bind brain MEC and thereby increase the recruitment of IE to the brain. We determined the cytoadherence properties of IE from children with CM, using the IE of children with uncomplicated malaria (UM) as comparator. In addition, associations between the binding phenotype and the expression of particular PfEMP1 variants with binding to the putative receptors EPCR, ICAM-1 and CD36 were assessed. During 3 malaria seasons in Malawi, IE were obtained from carefully characterised paediatric CM and UM cases. The IE were used with minimal in vitro expansion, to retain the PfEMP1 variant expressed, and binding to primary MEC, derived from brain or dermis, was determined using a micro-channel flow adhesion assay. Inhibitory antibodies and recombinant protein were used to assess the differential role of receptors and var transcripts were identified by qPCR and associated with binding phenotype.
The data, for the first time, provide direct evidence of preferentially binding of IE from CM patients to brain MEC. This binding is associated with specific PfEMP1 variants expressed, and provides a mechanism by which increased sequestration in the brain leads to CM.