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  • Review Article
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Neurological diseases

Pathogenesis of bacterial meningitis: from bacteraemia to neuronal injury

Nature Reviews Neuroscience volume 4, pages 376–385 (2003)Cite this article

Key Points

  • The sequence of events that are responsible for the onset of bacterial meningitis has been charted, particularly in the case of Escherichia coli. In general terms, it involves bacterial invasion of the meninges, increased permeability of the blood–brain barrier and pleocytosis, and neuronal injury. The molecular mechanisms that underlie these events remain poorly understood.

  • Bacterial invasion of the meninges requires a high level of bacteraemia. In addition, several bacterial and host molecules that are crucial for invasion have been identified. It has also been established that successful invasion depends on pathogen traversal as live bacteria. To this end, bacteria induce the reorganization of the host-cell cytoskeleton so that they are engulfed and protected from lysosomal activities. The relevant signalling pathways have begun to be mapped.

  • Once bacteria reach the cerebrospinal fluid, their proliferation leads to the increased permeability of the blood–brain barrier through the release of proinflammatory and toxic compounds, the nature of which has been elucidated in some cases.

  • A consequence of the increased permeability and pleocytosis is that neuronal injury takes place in response to increased intracranial pressure, oedema and toxicity. Several molecules have been proposed to elicit cell death, and targeting them constitutes a potential therapeutic strategy against the neurological sequelae that accompany meningitis.

  • The elucidation of the molecular pathways that participate in the bacterial infection of the meninges has provided us with new targets to develop preventive and therapeutic strategies. Future studies should continue characterizing these molecular events, and should establish whether other pathogenic bacteria follow similar rules.

Abstract

Bacterial meningitis is an important cause of mortality and morbidity despite advances in antimicrobial therapy. A key factor that contributes to the high prevalence of this condition is the incomplete understanding of its pathogenesis. Most cases of bacterial meningitis develop as a result of haematogenous spread, but it is unclear how circulating bacteria cross the blood–brain barrier, and how bacterial entry into the central nervous system results in inflammation and in complications such as pleocytosis, blood–brain barrier disruption and neuronal injury. Recent studies have shed light on the pathogenic mechanisms of bacterial translocation across the blood–brain barrier and the meningitis-associated complications. I propose that bacterial translocation, a key step for the development of meningitis, is the result of specific bacteria–host interactions, and that its complications are the result of multiple host responses to the invading microorganism.

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Figure 1: The sequential steps of bacteria–host interactions during the pathogenesis of bacterial meningitis.
Figure 2: Diagram of the microbial and host factors that contribute to successful crossing of Escherichia coli across brain microvascular endothelial cells (BMECs).
Figure 3: Electron micrograph of human brain microvascular endothelial cell monolayers 30 minutes after infection with Escherichia coli K1.
Figure 4: Intracellular movement of Escherichia coli-containing vacuoles in human brain microvascular endothelial cells (BMEC).
Figure 5: Host response during bacterial meningitis.

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Acknowledgements

This work was supported by NIH grants. I thank K. J. Kim for his help with figures.

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Authors and Affiliations

  1. Pediatric Infectious Diseases, Johns Hopkins Hospital, 600 North Wolfe Street, Park 256, Baltimore, 21287, Maryland, USA

    Kwang Sik Kim

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DATABASES

Genome Information Broker

Haemophilus influenzae

Listeria monocytogenes

Neisseria meningitidis

Streptococcus pneumoniae

LocusLink

37LRP

NF-κB

Swiss-Prot

CNF1

FimH

Ibe

OmpA

FURTHER INFORMATION

Encyclopedia of Life Sciences

bacterial meningitis

blood–brain barrier

Glossary

MORBIDITY

The incidence or prevalence of a disease in a population.

PLEOCYTOSIS

The presence of a greater than normal number of cells in the cerebrospinal fluid.

TIGHT JUNCTION

A belt-like region of adhesion between adjacent epithelial or endothelial cells. Tight junctions regulate paracellular flux, and contribute to the maintenance of cell polarity by stopping molecules from diffusing within the plane of the membrane.

PINOCYTOSIS

The cellular uptake of extracellular fluid. It involves the formation of caveolae by the cell membrane, which pinch off to form vesicles known as pinosomes in the cytoplasm.

CHOROID PLEXUS

A site of production of cerebrospinal fluid in the adult brain. It is formed by the invagination of ependymal cells into the ventricles, which become richly vascularized.

QUORUM SENSING

A mechanism used by many bacterial pathogens to detect bacterial cell numbers in host tissues. Cell densities are indicated by the concentration of autoinducers, which regulate the expression of specific genes.

ISOGENIC

A strain in which the chromosomes of different bacteria are identical.

S FIMBRIAE

Glycoprotein-binding structures of the membrane of Escherichia coli, which participates in bacterial binding to endothelial cells during the development of meningitis.

TRANSPOSON

Mobile DNA elements that can relocate within the genome of their hosts. Transposons can be used for various applications, including insertional mutagenesis, gene identification, gene tagging and DNA sequencing.

SIGNATURE-TAGGED TRANSPOSON MUTAGENESIS

A technique for detecting genes that are required for survival and growth in vivo that uses modified transposons to allow high-throughput screening of randomly generated mutants.

TRANS

Indicates a trans-acting element. A regulatory genetic element whose effects are independent of its position and, therefore, can be located in a different DNA molecule to the gene being regulated.

YEAST TWO-HYBRID SYSTEM

System used to determine the existence of direct interactions between proteins. It involves the use of plasmids that encode two hybrid proteins; one of them is fused to the GAL4 DNA-binding domain and the other one is fused to the GAL4 activation domain. The two proteins are expressed together in yeast and, if they interact, the resulting complex drives the expression of a reporter gene, commonly β-galactosidase.

DOMINANT-NEGATIVE

A mutant molecule that can form a heteromeric complex with the normal molecule, knocking out the activity of the entire complex.

CASPASES

A family of intracellular cysteine endopeptidases that have a key role in inflammation and mammalian apoptosis. They cleave proteins at specific aspartate residues.

INTRACISTERNAL

Administered directly into the cerebral ventricles.

LEUKOPENIA

A reduction in the number of white blood cells below 5000 mm−3.

CIRCUMVENTRICULAR ORGANS

Brain regions that have a rich vascular plexus with a specialized arrangement of the blood vessels. The junctions between the capillary endothelial cells are not tight in the blood vessels of these regions, allowing the diffusion of large molecules. These organs include the organum vasculosum of the lamina terminalis, the subfornical organ, the median eminence and the area postrema. Although not classed as circumventricular organs, the choroid plexus and leptomeninges are also highly vascularized and are rapidly activated by circulating pathogens.

CD14

The first lipopolysaccharide receptor to be characterized. It exists two forms: membrane CD14 (mCD14) and soluble CD14 (sCD14). mCD14 is present at the surface of myeloid cells and acts as a glycosylphosphatidylinositol (GPI)-anchored membrane glycoprotein, whereas sCD14 lacks the GPI anchor, but can bind lipopolysaccharide to activate cells that are devoid of mCD14, such as endothelial cells.

TOLL-LIKE RECEPTORS

A large family of receptors that are expressed at the surface of leukocytes and microglial cells. They are responsible for engaging the innate immune system in response to pathogens.

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Kim, K. Pathogenesis of bacterial meningitis: from bacteraemia to neuronal injury. Nat Rev Neurosci 4, 376–385 (2003). https://doi.org/10.1038/nrn1103

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