The Role of Circulating Endothelial Progenitor Cells (Cepcs) and Other Biomarkers in the Pathogenesis of Cerebral Malaria

Abstract

Cerebral malaria (CM) is known to be the most severe complication of Plasmodium falciparum infection. Despite effective anti-parasitic treatment, it remains a major cause of morbidity and mortality in infected children. Sequestration of infected red blood cells in the brain microvasculature, occlusion of blood flow, activation and subsequent damage of the endothelium are hallmarks of the pathogenesis of CM. This study sought to quantify and compare time course levels of cEPC and other biomarkers of endothelial injury and repair in Ghanaian children between the ages of 2 and 12 years with cerebral malaria, uncomplicated malaria as well as uninfected healthy controls. Participants with malaria were recruited from five main referral hospitals in Accra, Ghana and healthy uninfected controls from community schools around the hospitals. Matrix metalloproteinase-9 (MMP9), stromal cell-derived growth factor 1 (SDF-1), Angiopoietin 1 and 2, Endothelial protein C receptor (EPCR), thrombomodulin (TM) and Histidine Rich Protein 2 (HRP2) levels were also determined by enzyme-linked immunosorbent assay (ELISA) at the same time points in all study participants. Stability of cEPCs and CECs were assessed in whole blood stored in the cell preservative Cyto Chex BCT (C-C BCT) at 4oC and compared with that stored in ethylenediamine tetra acetic acid (EDTA) antocoagulant at baseline. CM patients showed a baseline mean percentage cEPC of 0.042% which increases to 0.117% at recovery from coma. cEPC levels in uncomplicated malaria (UM) and uninfected healthy controls (HC) were 0.147% and 0.83% respectively at baseline with no significant difference in time course. CEC levels in CM was higher (0.003%) at initial presentation compared with uncomplicated (0.001%) and uninfected healthy controls (0.0009%). However, CEC levels in UM patients spiked (0.009%) at day 7. HC maintained a low CEC levels in time course. SDF-1 levels remained unchanged in all study groups in time course whiles MMP9 levels were higher in UM patient compared with CM and HC at baseline. Angiopoietin 1 (Ang-1) levels were higher (5960pg/ml) in CM compared to UM (4041pg/ml) and HC (4909pg/ml) though not significant. TM, EPCR and HRP2 level was highest in CM compared with other groups at baseline. The study has shown that cEPCs and the mediators associated with their release and migration are very critical in the resolution of coma in children and has placed CM within the context of current paradigms of microvascular repair, offering strategies that could predict who is at risk of developing CM. Therapies that mobilize and improve cEPC function will therefore be of immense utility in the prevention and treatment of CM.