Contrasting pediatric and adult cerebral malaria: the role of the endothelial barrier

Abstract

Malaria affects millions of people around the world and a small subset of those infected develop cerebral malaria. The clinical presentation of cerebral malaria differs between children and adults, and it has been suggested that age-related changes in the endothelial response may account for some of these differences. During cerebral malaria, parasites sequester within the brain microvasculature but do not penetrate into the brain parenchyma and yet, the infection causes severe neurological symptoms. Endothelial dysfunction is thought to play an important role in mediating these adverse clinical outcomes. During infection, the endothelium becomes activated and more permeable, which leads to increased inflammation, hemorrhages, and edema in the surrounding tissue. We hypothesize that post-natal developmental changes, occurring in both endothelial response and the neurovascular unit, account for the differences observed in the clinical presentations of cerebral malaria in children compared with adults.

Keywords: adults; cerebral malaria; endothelial dysfunction; neurovascular unit; pediatric.

Figure 1. The effect of cerebral malaria on the blood–brain barrier (BBB) and the developing neurovascular unit. The BBB can be separated into the physiological BBB, where the endothelial cells are in close apposition to astrocyte end processes and pericytes, and the neuroimmunological BBB, which has a perivascular space separating the endothelial cells from the astrocytic foot processes. During malaria infection, the endothelium becomes activated leading to both transcellular and paracellular leak. The neurovascular unit, which makes up the BBB, undergoes marked changes during development which may impact the pathogenesis of cerebral malaria, including: synaptic pruning, myelination, immune system maturation, maturation and differentiation of glial cells, increased expression of tight junction proteins, and ultimately improved endothelial barrier function.

Figure 2. Key molecular pathways that govern endothelial barrier function and may play a role in the endothelial dysfunction occurring during malarial infection. (1) Ang-1 mediated signaling inhibits NFκB, prevents the internalization of VE-Cadherin, promotes nitric oxide formation and promotes endothelial cell survival. Conversely, Ang-2 competes with Ang-1 for Tie2 binding after being released during Weibel–Palade (WP) body exocytosis. Ang-2 antagonizes the effects of Ang-1. (2) Nitric oxide inhibits exocytosis of WP bodies. (3) Sphingosine-1-phosphate (S1P) stabilizes proteins that make up tight junctions, adherens junctions and focal adhesions. (4) Slit-Robo4 signaling promotes VE-cadherin localization to the plasma membrane and inhibits VEGF mediated endocytosis of VE-cadherin. EC, endothelial cell; ECM, extracellular matrix.