Authors

N E Andoh²; M F Stins¹; S J Chakravorty²;  ¹ Johns Hopkins Medical School, Baltimore, USA;  ² School of Life Sciences, Keele University

Discussion

Plasmodium falciparum-infected red blood cells (PRBC) sequestered in brain microvasculature, disruption of the blood brain barrier (BBB) and long term neurological symptoms are associated with cerebral malaria (CM).

This study investigates the impact of PRBC on the cellular components of the BBB in CM, using an in vitro tandem model comprising human brain endothelial cell (HBEC) (luminal side) and human astrocytes (basolateral side), in a transwell system.  This model mimics the endothelial cells and astrocyte end feet, the main components of the BBB neurovascular unit (NVU) and the interface between the blood and the neuronal cells of the brain.

Supernatants and lysates harvested from the coculture of PRBC and HBEC (in vitro model of sequestration), induced a significant increase in the permeability of the endothelial barrier and demonstrated the presence of inflammatory mediators including proteases, MCP-1 and ICAM-1.

Endothelial activation and astrogliosis in the NVU was evaluated in this study, represented by release of ADAMTS4 and glial fibrillary acidic protein (GFAP), respectively.  Our studies showed that endothelial-derived factors, produced during sequestration mediated a marked increase in the release of ADAMTS4, both luminally and basolaterally in the NVU.  Interestingly, astrocyte-derived GFAP showed a marked increase only on the luminal side of the NVU, most likely from damage to the astrocyte end feet.

We propose that endothelial-derived inflammatory mediators, produced by the BBB in response to PRBC, can induce astrocyte injury in the NVU, during episodes of CM.  This astrocyte damage is a key event in the development of neuronal and synaptic dysfunction that leads to the neurological symptoms in CM.