Review Article | Published:

Mechanisms of microbial traversal of the blood–brain barrier

Nature Reviews Microbiology volume 6, pages 625634 (2008) | Download Citation

Subjects

Abstract

Central nervous system (CNS) infections continue to be an important cause of morbidity and mortality. Microbial invasion and traversal of the blood–brain barrier is a prerequisite for CNS infections. Pathogens can cross the blood–brain barrier transcellularly, paracellularly and/or in infected phagocytes (the so-called Trojan-horse mechanism). Consequently, pathogens can cause blood–brain barrier dysfunction, including increased permeability, pleocytosis and encephalopathy. A more complete understanding of the microbial–host interactions that are involved in microbial traversal of the blood–brain barrier and the associated barrier dysfunction should help to develop new strategies to prevent CNS infections.

Key points

  • Microbial invasion and traversal of the blood–brain barrier is a prerequisite for meningitis and the associated blood–brain barrier dysfunction. Our current knowledge has been charted using Escherichia coli, with an emphasis on similarities and differences between different pathogens.

  • Transcellular penetration of the blood–brain barrier has been demonstrated for most meningitis-causing microorganisms, but the underlying mechanisms differ for different organisms.

  • E. coli invasion of the blood–brain barrier requires a high level of bacteraemia, as well as several bacterial and host factors. These microorganism–host interactions are unique to the blood–brain barrier and the relevant interactions have begun to be identified for E. coli and other meningitis-causing microorganisms.

  • Microbial binding to, and invasion of, the blood–brain barrier occurs through ligand–receptor interactions. Different microbial ligands interact with the same receptors, but the relevant interactions that are involved in traversal of the blood–brain barrier remain incompletely understood.

  • Microbial invasion and traversal of the blood–brain barrier requires rearrangement of the host cell cytoskeleton. Different microorganisms use different signal-transduction mechanisms to effect this rearrangement.

  • Central nervous system-infecting microorganisms induce blood–brain barrier dysfunction, but the underlying mechanisms differ from those that are involved in microbial binding to or invasion of the blood–brain barrier.

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Acknowledgements

The information contained in this Review is derived from studies carried out by members of the author's laboratory and his collaborators' laboratories. Work in the laboratory of K.S.K. was supported by National Institutes of Health grants.

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  1. Division of Pediatric Infectious Diseases, Johns Hopkins University School of Medicine, 200 North Wolfe Street, Room 3157, Baltimore, Maryland 21287, USA.  kwangkim@jhmi.edu

    • Kwang Sik Kim

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Glossary

Astrocyte

A star-shaped glial cell that supports the tissue of the central nervous system.

Pericyte

A cell that is found around capillaries and is related to smooth muscle cells. Pericytes surround the endothelium as single cells. Association with pericytes reduces endothelial apoptosis and stabilizes the vasculature.

Pinocytosis

The cellular uptake of extracellular fluid. Involves the formation of caveolae by the cell membrane that pinch off to form vesicles in the cytoplasm.

Microglial cell

An immune cell of the central nervous system that is derived from mesodermal precursor cells and could be of haematopoietic lineage.

Choroid plexus

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

AB-type toxin

A bacterial toxin that modifies target proteins within the cytosol of host cells and is composed of two domains: one that is responsible for the enzymatic activity (A) and one that is responsible for cell-receptor binding (B).

Pleocytosis

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

Fibrinolytic system

A broad spectrum of proteolytic enzymes that includes the plasminogen activator system and plasmin. Plasmin and plasmin activators proteolytically degrade the extracellular matrix.

Encephalopathy

Brain dysfunction that is associated with alterations of the neural microenvironment and results from metabolic, toxic, vascular, infectious and/or inflammatory insults.

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