Infections in the Developing Brain: The Role of the Neuro-Immune Axis

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.

Translating metagenomics into clinical practice of complex paediatric neurological presentations

“…This is particularly true for immunocompromised hosts who are at higher risk of unusual CNS pathogens, which may not be detected by standard investigations. Immunocompromised patients are also at risk of CNS immune dysregulation, with, or as a sequela of active infection, and who are known to suffer worse outcomes when untreated 15,16 .…”

The role of biomaterials in degenerative diseases

“…In the homeostatic baseline, neuroimmune signaling interacts with neurons and regulates the neural function and synaptic plasticity (8). During neuroimmune activation, pathological conditions activate endothelial cells, microglia, and astrocytes, which produce cytokines and chemokines (9). As a result, the immune mechanism operates without immune cells entering damaged tissue (10).…”

Developing brain under renewed attack: viral infection during pregnancy

“…Glial cells namely astrocytes and microglia play an important role during development enabling functional neural circuitry formation, maturation and maintenance ( Lago-Baldaia et al, 2020 ; Eze et al, 2021 ). In response to infection and cytokine release, glial cells become activated showing a pro-inflammatory state to improve neuroprotection and homeostasis ( Dahm et al, 2016 ; Cornish et al, 2020 ; Elgueta et al, 2022 ; Kim et al, 2022 ). However, such early life stresses can be damaging to the developing brain due to a dysregulated glial functioning (e.g., impaired phagocytic activity, over/prolonged activation) and blunted glial development.…”