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  • Review Article
  • Published:

A hitchhiker's guide to the nervous system: the complex journey of viruses and toxins

Nature Reviews Microbiology volume 8, pages 645–655 (2010)Cite this article

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This article has been updated

Key Points

  • The central nervous system is often referred to as immune privileged but is nonetheless the target of numerous neurotropic microbial agents.

  • Some viruses and toxins can enter nerve terminals by binding specific cellular receptors found on neuromuscular junctions and sensory-nerve endings.

  • Following internalization at synapses, pathogens can access the machinery regulating long-range axonal transport to reach the neuronal cell bodies and propagate.

  • The mode of axonal transport differs depending on the microbial agent; some can recruit molecular motors directly, whereas others use endosomal pathways.

  • In the neuronal cell body, viruses undergo different fates: they may become latent, or they may continue their journey into a new neuron.

  • Neurotropic viruses and toxins undergoing axonal transport in neurons can be used for neuronal tracing and gene therapy.

Abstract

To reach the central nervous system (CNS), pathogens have to circumvent the wall of tightly sealed endothelial cells that compose the blood–brain barrier. Neuronal projections that connect to peripheral cells and organs are the Achilles heels in CNS isolation. Some viruses and bacterial toxins interact with membrane receptors that are present at nerve terminals to enter the axoplasm. Pathogens can then be mistaken for cargo and recruit trafficking components, allowing them to undergo long-range axonal transport to neuronal cell bodies. In this Review, we highlight the strategies used by pathogens to exploit axonal transport during CNS invasion.

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Figure 1: Neuronal architecture and axonal transport.
Figure 2: Axonal transport of viruses and toxins.
Figure 3: Somatodendritic sorting of microbial agents.

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Change history

  • 13 August 2010

    The figure 3 citation has been deleted in the following sentence: "The binding fragment of TeNT (TeNT HC) 66 (BOX 3) is internalized along with CAV-2 and CAR45 in clathrin-coated vesicles and progresses from Rab5-positive to Rab7-positive endocytic compartments, which undergo axonal transport (see below)". Also, the author's surname in the links box has been corrected to Schiavo.

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Acknowledgements

We thank the members of the G.S. and E.J.K. laboratories and J. Schwarz for constructive comments. Work in the G.S. laboratory is supported by Cancer Research UK, the Motor Neurone Disease Association, the Jean Coubrough Charitable Trust and funding from the European Community's 7th Framework Programme (FP7/2007–2013; grant 222992 — BrainCAV). The E.J.K. laboratory is supported by BrainCAV, the French Agence National de la Recherche, the Region Languedoc Roussillon, the Fondation de France and the Association Française contre les Myopathies. E.J.K. and S.S. are Institut National de la Santé et de la Recherche Médicale (INSERM) fellows.

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Authors and Affiliations

  1. Institut de Génétique Moléculaire de Montpellier, CNRS UMR 5535, Montpellier Cedex 5, 34293, France

    Sara Salinas & Eric J. Kremer

  2. Universités de Montpellier I & II, Montpellier, 34090, France

    Sara Salinas & Eric J. Kremer

  3. Molecular NeuroPathobiology Laboratory, Cancer Research UK London Research Institute, London, WC2A 3LY, UK

    Giampietro Schiavo

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DATABASES

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RABV

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HIV-1

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Glossary

Tetanus

A spastic paralysis resulting from the inhibition of neurotransmitter release at the level of inhibitory interneurons. This inhibition is caused by intoxication with TeNT (a protein toxin produced by Clostridium tetani), which is taken up at neuromuscular junctions.

Botulism

A flacid paralysis resulting from the inhibition of acetylcholine release at neuromuscular junctions, mediated by BoNTs. These toxins act by cleaving the synaptic components that mediate fusion of synaptic vesicles to the plasma membrane.

Synaptogenesis

Formation of synapses in the central and peripheral nervous systems. This process initiates early in development and continues throughout adulthood.

Axonal retrograde transport

Traffic of molecules and organelles from nerve terminals to cell bodies. This mechanism is mainly microtubule-dependent and involves the molecular motor cytoplasmic dynein.

Axonal anterograde transport

Traffic of molecules and organelles from cell bodies to nerve terminals. This mechanism is mainly microtubule-dependent and involves molecular motors of the kinesin family.

Neurotrophin

One of a family of growth factors involved in neuronal growth, differentiation and survival. A classical example is NGF, which is involved in the survival of specific neurons during development.

Neuromuscular junction

Specialized synapse that connects motor neurons to muscle fibres. Axon terminals contact muscle fibres through motor end plates, which are specialized regions that are responsible for the transmission of electrical signals.

Lipid raft

Microdomain of the plasma membrane that is enriched in cholesterol and sphingolipids. Certain classes of GPI-anchored and transmembrane proteins acting as virus and toxin receptors seem to be concentrated in these structures.

Microtubule-organizing centre

Site of microtubule nucleation in eukaryotic cells; it organizes flagella, ciliae and spindle poles, and it is closely associated with the Golgi apparatus.

Microfusion event

Local membrane fusion triggered by the interaction between certain viral proteins and surface receptors.

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Salinas, S., Schiavo, G. & Kremer, E. A hitchhiker's guide to the nervous system: the complex journey of viruses and toxins. Nat Rev Microbiol 8, 645–655 (2010). https://doi.org/10.1038/nrmicro2395

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