An in vitro study of the modulation of astrocytes in the blood brain barrier during cerebral malaria


A J Ogbolosingha2; N E Andoh2; M F Stins1; S J Chakravorty2
1 Johns Hopkins Medical School, Baltimore, United States;  2 School of Life Sciences, Keele University, UK


Cerebral malaria (CM) is the most life-threatening complication of Plasmodium falciparum infection. P. falciparum-infected red blood cells (PRBC) sequester within microvasculature adhering to endothelial cells (EC) of the blood brain barrier (BBB) resulting in the activation and disruption of the endothelium. Consequently, there is entry of blood borne toxins, inflammatory molecules, parasite products and water into the brain parenchyma leading to cerebral perivascular oedema and long term neurological sequelae. The current study aims to investigate the activation of astrocytes following sequestration of PRBC in the endothelium of the BBB. We coculture EC and PRBC that mimics P. falciparum sequestration in the brain. Previous findings from our laboratory has shown that supernatants harvested from EC and PRBC cocultures mediates the activation of the BBB endothelium marked by increased expression of ICAM-1. The current study, an advanced in vitro model of the BBB consisting of EC and astrocytes grown in tandem on a transwell filter shows that the underlying astrocytes ensheathing the endothelium with their end feet are also activated by the EC and PRBC coculture supernatant as seen in the upregulation of astrocyte ICAM-1 and the astrocyte marker, GFAP. Interestingly, the water mobilising membrane protein, aquaporin 4 (AQP4), expressed predominantly in the end feet of astrocytes was concomitantly upregulated by the supernatant, suggesting an increased mobilisation of water into the brain, thus causing cerebral oedema. Collectively, the data shows the activation of the endothelium following PRBC sequestration leads to downstream consequences such as activation of the astrocytes. The increased expression of AQP4, demonstrated in these studies, is indicative of a possible mechanism for the development of the cerebral oedema prevalent in paediatric CM patients.

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