Abstract
Central nervous system (CNS) infections occur more commonly in young children than in adults and pose unique challenges in the developing brain. This review builds on the distinct vulnerabilities in children's peripheral immune system (outlined in part 1 of this review series) and focuses on how the developing brain responds once a CNS infection occurs. Although the protective blood-brain barrier (BBB) matures early, pathogens enter the CNS and initiate a localized innate immune response with release of cytokines and chemokines to recruit peripheral immune cells that contribute to the inflammatory cascade. This immune response is initiated by the resident brain cells, microglia and astrocytes, which are not only integral to fighting the infection but also have important roles during normal brain development. Additionally, cytokines and other immune mediators such as matrix metalloproteinases from neurons, glia, and endothelial cells not only play a role in BBB permeability and peripheral cell recruitment, but also in brain maturation. Consequently, these immune modulators and the activation of microglia and astrocytes during infection adversely impact normal neurodevelopment. Perturbations to normal brain development manifest as neurodevelopmental and neurocognitive impairments common among children who survive CNS infections and are often permanent. In part 2 of the review series, we broadly summarize the unique challenges CNS infections create in a developing brain and explore the interaction of regulators of neurodevelopment and CNS immune response as part of the neuro-immune axis.
Highlights
The development of the central nervous system (CNS) is a tightly regulated complex and dynamic process
The lower panel summarizes the roles of resident immune cells and secreted immune mediators (TNF super family, matrix metalloproteinases (MMPs), IL-6) during normal brain development compared to dysregulated brain development during Central nervous system (CNS) infection
During the CNS immune response to infection, microglia, astrocytes, neurons and brain microvascular endothelial cells (BMECs) secrete a plethora of cytokines, chemokines and MMPs
Summary
The development of the central nervous system (CNS) is a tightly regulated complex and dynamic process. It is suggested that the CNS is a site of active, highly regulated immune surveillance [25] The lower panel summarizes the roles of resident immune cells (microglia and astrocytes) and secreted immune mediators (TNF super family, MMP, IL-6) during normal brain development compared to dysregulated brain development during CNS infection. Astrocytic ephrin-A3 activates EphA4 receptors on neuronal dendritic spines (DS) and regulates DS morphology and lifetime [68, 69] Many of these molecules are being examined for their roles during CNS injury and infection. Postnatal activation of astrocytic TLR4-MyD88 promotes hippocampal excitatory synaptogenesis and dendritic branching which may underpin increased seizure susceptibility accompanying many CNS infections [85]
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