Review Article | Published:

A journey into the brain: insight into how bacterial pathogens cross blood–brain barriers

Nature Reviews Microbiology volume 15, pages 149159 (2017) | Download Citation

Abstract

The blood–brain barrier, which is one of the tightest barriers in the body, protects the brain from insults, such as infections. Indeed, only a few of the numerous blood-borne bacteria can cross the blood–brain barrier to cause meningitis. In this Review, we focus on invasive extracellular pathogens, such as Neisseria meningitidis, Streptococcus pneumoniae, group B Streptococcus and Escherichia coli, to review the obstacles that bacteria have to overcome in order to invade the meninges from the bloodstream, and the specific skills they have developed to bypass the blood–brain barrier. The medical importance of understanding how these barriers can be circumvented is underlined by the fact that we need to improve drug delivery into the brain.

Key points

  • The blood–central nervous system (CNS) barriers are tight and protect the brain parenchyma from insults, including those of infectious origin. This barrier function is due to the presence of tight junctions between the endothelial cells of the brain. The formation of these junctions is the consequence of interactions inside the neurovascular unit.

  • There are two blood–CNS barriers that can potentially be circumvented by bacterial pathogens: the blood–brain barrier (BBB) and the blood–cerebrospinal fluid barrier (BCSFB). The BCSFB corresponds to the choroid plexuses and the microvessels of the leptomeninges.

  • Bacteria can invade the meninges from the bloodstream through the choroid plexuses or directly through the microvessels of the leptomeninges and/or the brain parenchyma. In the case of crossing from parenchyma vessels, bacteria are drained to the subarachnoid space through the glymphatic pathway.

  • Regardless of the site of crossing, meningeal invasion requires the crossing of two cellular barriers: an endothelial monolayer (in the choroid plexus or in the brain parenchyma and/or leptomeninges) followed by an epithelial monolayer (the choroid plexus ependyma, or the leptomeningeal monolayer of the pia mater or of a subarachnoid trabecula).

  • A limited number of blood-borne bacteria can cross the blood–CNS barriers and cause meningitis. The extracellular pathogens that are involved are usually Neisseria meningitidis, Streptococcus pneumoniae or, in newborns, group B Streptococcus and Escherichia coli K1.

  • Regardless of the mechanisms that are used to invade the meninges from the bloodstream, the level of bacteraemia plays a key part in meningeal tropism.

  • The extracellular bacteria interact directly with the blood–CNS barriers.

  • N. meningitidis is believed to cross the blood–CNS barriers by interacting with the leptomeninges and/or brain microvessels, and to open intercellular junctions following signals that are induced by the adhesion of bacteria to the endothelial cells.

  • S. pneumoniae invades the meninges following interaction with the brain microvessels and is believed to transcytose through the endothelial cells following interactions with several host cell receptors.

  • E. coli is believed to transcytose through endothelial cells, to have several attributes that enable it to adhere to endothelial cells and to induce signalling events that lead to bacterial invasion.

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Acknowledgements

The laboratory of X.N. is supported by the Fondation pour la Recherche Médicale, The French Agence Nationale de la Recherche, INSERM (French Institut National de la Santé et de la Recherche Médicale), CNRS (French Centre National de la Recherche Scientifique) and the University Paris Descartes, France.

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Affiliations

  1. Institut National de la Santé et de la Recherche Médicale (INSERM) U1151, Institut Necker-Enfants Malades, 14 Rue Maria Helena Vieira da Silva, 75014 Paris, France.

    • Mathieu Coureuil
    • , Hervé Lécuyer
    •  & Xavier Nassif
  2. Le Centre National de la Recherche Scientifique (CNRS) UMR 8253, 75014 Paris, France.

    • Mathieu Coureuil
    • , Hervé Lécuyer
    •  & Xavier Nassif
  3. Faculté de Médecine, Université Paris Descartes, 75014 Paris, France.

    • Mathieu Coureuil
    • , Hervé Lécuyer
    • , Sandrine Bourdoulous
    •  & Xavier Nassif
  4. Laboratoire de Microbiologie Clinique, Hôpital Necker-Enfants Malades, 75015 Paris, France.

    • Hervé Lécuyer
    •  & Xavier Nassif
  5. Institut National de la Santé et de la Recherche Médicale (INSERM) U1016, Institut Cochin, 22 Rue Méchain, 75014 Paris, France.

    • Sandrine Bourdoulous
  6. Le Centre National de la Recherche Scientifique (CNRS) UMR 8104, 75014 Paris, France.

    • Sandrine Bourdoulous

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The authors declare no competing financial interests.

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Correspondence to Xavier Nassif.

Glossary

Tight junctions

Regions of neighbouring cells that are very closely associated, such that the cell membranes join together to form a barrier that is virtually impermeable to fluid. The major types of protein that are involved in these junctions are the claudins and occludin. These proteins associate with peripheral membrane proteins such as zona occludens 1 (ZO1), which are located on the intracellular side of the plasma membrane and which anchor the strands of membrane claudins and occludin to the actin cytoskeleton.

Subarachnoid space

The anatomical space between the arachnoid mater and the pia mater. It is occupied by spongy tissue that consists of trabeculae (delicate, vascularized connective tissue filaments that extend from the arachnoid mater and blend into the pia mater) and intercommunicating channels in which the cerebrospinal fluid is contained.

Venous sinuses

Venous channels that are located inside the dura mater of the brain. They can be conceptualized as trapped epidural veins. Unlike other veins in the body, they run along, rather than parallel to, arteries.

Ventricular ependyma

The thin epithelial lining of the ventricular system of the brain. These cells are in continuity with the epithelium of the choroid plexuses.

Transcytotic vesicles

Vesicles that transport bacteria or macromolecules across a cell, from the apical to the basolateral membrane.

Glia limitans

A thin barrier that is formed of astrocyte endfeet and the associated parenchymal basal lamina that surrounds the brain and spinal cord. This barrier constitutes the outermost layer of neural tissue.

Purpura fulminans

A syndrome that involves intravascular thrombosis and haemorrhagic infarction of the skin that is rapidly progressive, accompanied by vascular collapse and disseminated intravascular coagulation. Neisseria meningitidis infections are the main cause of infectious purpura fulminans.

Exocytosis

The counterpart of endocytosis. In the context of this Review, exocytosis corresponds to active transport out of cells.

G protein-coupled receptor

(GPCR). A member of a large family of receptors that sense molecules outside the cell and activate intracellular signal transduction pathways. Ligand binding causes a conformational change in the GPCR, which allows it to act as a guanine nucleotide exchange factor. The GPCR can then activate an associated G protein, the α-subunit of which affects intracellular signalling proteins or targets functional proteins.

Adherens junctions

Protein complexes that occur at cell–cell junctions in epithelial and endothelial tissues and that are more basal than tight junctions. These junctions are formed by the association of cadherins.

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https://doi.org/10.1038/nrmicro.2016.178

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