The brain is composed of a highly diverse array of neurons and glial cells that functionally interact to support healthy cognitive and motor functions. To satisfy the high energy requirements of the brain, the cerebral parenchyma is heavily vascularized, providing continuous access of nutrients and oxygen while also facilitating the removal of waste products. This is achieved through a highly specialized vascular interface known as the blood-brain barrier (BBB) that precisely controls influx of ions and molecules into the brain while preventing the entry of toxic agents and pathogens from the blood (Obermeier et al., 2013). Despite the presence of this selective barrier, parasites have developed complex interactions with the BBB that can lead to either (a) widespread dysfunction of the brain microvasculature or (b) transmigration of parasites into the brain parenchyma.Cerebral malaria is a paradigmatic example of parasite-induced brain microvascular pathogenesis without crossing into the brain parenchyma. It is characterized by extensive cytoadhesion of Plasmodium falciparum-infected red blood cells (iRBC) to endothelial brain receptors, such as intracellular adhesion molecule 1 (ICAM-1; Ockenhouse et al., 1992) or endothelial protein C receptor (EPCR;Turner et al., 2013). P. falciparum-iRBC interaction with EPCR has been proposed as one of the main contributors to brain microvascular dysfunction, by blocking cytoprotective, anti-inflammatory, and junctional stabilizing pathways regulated by this endothelial receptor (Bernabeu & Smith, 2017). Another barrier-disruptive mechanism that has been proposed is the release of toxic components upon P. falciparum-iRBC egress of new asexual infective parasites, known as merozoites (Gallego-Delgado et al., 2016;Tripathi et al., 2007). These toxic agents might include parasite histones or proteins such as P. falciparum
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