Chapter 16 : Pathogenesis of Pneumococcal Meningitis

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Pneumococcal meningitis is still an unresolved problem in clinical medicine. A number of recent studies demonstrate the unfavorable outcome of pneumococcal meningitis, reporting mortality rates up to 40%. Most models are based on the injection of pneumococci or their inflammatory components into the subarachnoidal space, followed by the hallmarks of meningitis: the influx of leukocytes into CSF, development of brain edema, intracranial pressure, and typical histological changes. Inhibition of TNF-α results in decreased leukocyte invasion in pneumococcal meningitis. Deficiency in interleukin-18 (IL-18), another cytokine cleaved by caspase-1, results in reduced inflammation and better survival in experimental pneumococcal meningitis. In pneumococcal meningitis, all these steps happen in the arachnoidal microvessels and the triggers for leukocyte-endothelium interactions include histamine and cytokines. In an infant rat model of pneumococcal meningitis, Matrix metalloprotease (MMP) inhibitors decreased inflammatory alterations, including neuronal damage. Different antioxidative strategies interfering with generation of reactive oxygen species attenuate intracranial complications, including neuronal damage in pneumococcal meningitis in the adult as well as in the infant animal model. Inhibition of inducible nitric oxide synthase (NOS) ameliorates inflammation in pneumococcal meningitis. In the rabbit model, apoptosis is a predominant mechanism of neuronal damage and focuses on the dentate gyrus. Hippocampal neurons of patients who have died from pneumococcal meningitis show the morphological criteria of apoptosis and active caspase-3. Although the beneficial effect of dexamethasone has been shown in clinical trials, it should be considered that, at least in experimental models, this drug augments apoptosis in the dentate gyrus.

Citation: Weber J. 2004. Pathogenesis of Pneumococcal Meningitis, p 238-251. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch16

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Tumor Necrosis Factor alpha
Transforming Growth Factor beta
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Image of FIGURE 1

Schematic anatomy of the blood-brain barrier. (A) Cerebral vessels mark the blood-brain barrier as formed by tight junctions and supporting cells. (B) In detail, the barrier at the choroid plexus is formed at the layer of epithelial CSF secreting cells that overlay fenestrated endothelial cells. Translocated bacteria are indicated as small ovals. (C) The barrier at the cerebral capillary is formed by tight junctions between endothelial cells that are supported by astrocytes. Translocated bacteria are indicated as small ovals.

Citation: Weber J. 2004. Pathogenesis of Pneumococcal Meningitis, p 238-251. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch16
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Image of FIGURE 2

Autocrine loop enhancing transmigration of pneumococci across the blood-brain barrier. Pneumococcal cell wall (PCW) induces endothelial cells to produce TNF and NO. These in turn further activate the neighboring cells to produce more NO and up-regulate the PAF receptor (PAFr) and ICAM-1. PAF receptor enables bacterial translocation into the CSF, while ICAM-1 recruits leukocytes.

Citation: Weber J. 2004. Pathogenesis of Pneumococcal Meningitis, p 238-251. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch16
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Image of FIGURE 3

Schematic of two pathways of neuronal injury in pneumococcal meningitis. ICP, intracranial pressure; ROS, reactive oxygen species; RNI, reactive nitrogen intermediates.

Citation: Weber J. 2004. Pathogenesis of Pneumococcal Meningitis, p 238-251. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch16
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