The Potential Roles of Glial Cells in the Neuropathogenesis of Cerebral Malaria

Abstract

Cerebral malaria (CM) is a severe neurological complication of malaria caused by the Plasmodium falciparum parasite. It is one of the leading causes of death in children under 5 years of age in Sub-Saharan Africa. CM is associated with blood-brain barrier disruption and long-term neurological sequelae in survivors of CM. Despite the vast amount of research on cerebral malaria, the cause of neurological sequelae observed in CM patients is poorly understood. In this article, the potential roles of glial cells, astrocytes, and microglia, in cerebral malaria pathogenesis are reviewed. The possible mechanisms by which glial cells contribute to neurological damage in CM patients are also examined.

Keywords: Plasmodium; astrocytes; blood-brain barrier; cerebral malaria; glial cells; microglia.

Figure 1

Schematic representation of the Neurovascular Unit (NVU). The NVU is made up of an endothelium, basement membrane, pericytes, microglia, astrocytes and neurons.

Figure 2

Potential mechanisms that could be responsible for the neurological sequelae observed in survivors of CM. During CM, sequestration of PRBC to the BBB can result in the activation of the endothelial cells of the BBB. This leads to an increased expression of adhesion molecules on endothelial cells, increased release of proinflammatory cytokines and chemokines, increased miR155 expression and internalisation of PRBC by endothelial cells. Also, CD8⁺ T cells in the perivascular space can release granzyme that can induce apoptosis of endothelial cells. All these factors can cause BBB disruption resulting in the movement of parasite-derived factors such as Hz, EVs, cytokines and chemokines into the brain causing activation of microglia and astrocytes. Increased expression of AQP4 can result in the influx of fluid causing swelling of astrocytes and this can result in oedema. Activation of glial cells can be beneficial or damaging depending on the type of injury. Activated glial cells can release cytokines and chemokines such as IL-1β, TNFα, CXCL10, CXCL9 that can impair neuronal function. This can result in long term neurological sequelae in CM survivors. On the other hand, activation of glial cells could protect neurons during CM. The release of NO by microglia and NGB by astrocytes can protect neurons from neuronal damage. Understanding the mechanisms that are involved in glial activation and neuronal damage during CM can lead to the development of adjunct therapies that can help alleviate the burden of neurological sequelae in patients who survive CM.