Abstract
Under physiologic conditions, the brain is a microbiologically sterile site and is protected from infection by highly specialized barriers, including the hard bony skull, the tough dura mater, and the restrictive blood–brain barrier (BBB). Host defense mechanisms in the central nervous system (CNS) are limited and tightly regulated. Peripheral immune cells and plasma proteins are largely excluded from the brain parenchyma. Once they have breached the protective barriers and entered the CNS, bacteria multiply within the cerebrospinal fluid space (CSF) highly efficiently exhibiting similar kinetics as in vitro and reaching concentrations of up to 109 CFU/mL.
In response to the multiplying bacteria and their components, i.e., cell wall fragments, lipopolysaccharides, teichoic and lipoteichoic acids, peptidoglycans, bacterial DNA, and other cytosolic factors, resident cells in the perivascular space and the meninges release pro-inflammatory signaling molecules. Tumor necrosis factor-α, interleukin-1β, and IL-6 are released early on and trigger a cascade of other inflammatory mediators, including a variety of cytokines, chemokines, platelet-activating factor, antimicrobial peptides, prostaglandins, matrix metalloproteinases, nitric oxide, and reactive oxygen species initiating a self-perpetuating inflammatory cascade.
The immediate consequences of the intense inflammatory reaction are a massive influx of leukocytes, the breakdown of the blood–brain barrier with the formation of brain edema, and alterations of the cerebral blood flow. This overshooting inflammatory reaction to the invading pathogens causes damage to the brain parenchyma as collateral damage and is the driving pathophysiologic mechanism of inflammatory inner ear damage, brain cortical ischemic injury, and hippocampal apoptosis, the most frequent histopathological correlates of the neurofunctional sequelae of bacterial meningitis.
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This work was supported by grant no. 162583 (to SLL) from the Swiss National Science Foundation.
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Agyeman, P., Grandgirard, D., Leib, S.L. (2017). Neuroinflammation in Bacterial Meningitis. In: Lyck, R., Enzmann, G. (eds) The Blood Brain Barrier and Inflammation. Progress in Inflammation Research. Springer, Cham. https://doi.org/10.1007/978-3-319-45514-3_10
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