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

Ogbolosingha, Atieme Joseph

Authors

Atieme Joseph Ogbolosingha



Contributors

Srabasti Chakravorty
Supervisor

Abstract

Cerebral malaria (CM) is the most life-threatening complication of Plasmodium falciparum (Pf) infection. A key hallmark of CM is the sequestration of Pf infected red blood cells (PRBC) to the human brain endothelial cells (HBEC) of the blood brain barrier (BBB). This often leads to BBB disruption and cerebral oedema resulting in long term neurological complications in most survivors. It is unclear how PRBC which remains in the microvasculature and does not infect cells of the brain parenchyma causes such remarkable alterations in the brain parenchyma. This study was aimed at investigating the indirect effect of PRBC sequestration on the BBB with focus on the alteration of astrocytes and aquaporin 4 (AQP4) water channel which is a water mobilising protein expressed in astrocytes. This novel study was performed using an advanced in vitro BBB model consisting of endothelial cells and astrocytes in tandem which closely reproduces the in vivo conditions. To achieve the research aims, HBEC and PRBC were cocultured to mimic Pf sequestration and the supernatant which represents inflammatory factors released by the endothelium was harvested. The treatment of the HBEC-astrocyte tandem BBB model with the HBEC-PRBC supernatant disrupted the barrier and activated astrocytes marked by significant upregulation of astrocyte ICAM-1. This increase was associated with a concomitant downregulation of s100-ß with a 62% reduction in fold change compared to the control. Also, there was a trend towards increase in GFAP and ADAMTS-1 expression, but these were not significant (p<0.05). Remarkably, the supernatants also induced a small but significant upregulation of AQP4 with over 76%-fold change. Interestingly, a pilot study using severe and cerebral malaria patient sera also disrupted the barrier and showed an increasing trend towards astrocyte activation and AQP4 upregulation, although these were not statistically significant changes. Collectively, the activation of astrocytes and AQP4 upregulation may lead to the secretion of inflammatory mediators that could impair neuronal function and potentially contribute to the neurological sequelae in CM patients.

Thesis Type Thesis
Publication Date 2022-06
Additional Information Embargo on access until 25 May 2027 - The thesis is due for publication, or the author is actively seeking to publish this material.




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