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Microbes' roadmap to neurons

Key Points

  • Infections by microbes cause major diseases in the nervous system but are relatively neglected in the neuroscience community.

  • Mechanisms have evolved by which microbes can bypass the barriers that protect the nervous system and target neuronal populations in various regions of the brain.

  • Immune responses in the nervous system are generally not robust. This allows microbes to hide and survive in this relatively protective environment, but can also lead to rapid, life-threatening infections.

  • Knowledge on the fundamental cellular mechanisms used by microbes to propagate to the nervous system is important for developing host-directed drugs as adjunctive treatments with antimicrobial drugs.

  • Infections with microbes can have late-onset effects on nervous system functions, leading to behaviour changes and epilepsy. Research on the pathogenic events during these long latency periods could aid the development of strategies to prevent the appearance of these signs of disease.

  • Studies on the interactions between neurons and microbes also provide powerful tools to decipher basic neuronal functions and molecular sorting mechanisms.

Abstract

The nervous system is protected by barriers that restrict the invasion of pathogens. Nevertheless, mechanisms have evolved by which microbes can pass these barriers, enter and exit neurons and target various regions of the nervous system. In the brain, immune responses to pathogens are generally not robust, so microbes can hide and survive or, conversely, cause severe uncontrolled infections. Depending on their sites of entry and the regions that they target, microbes can cause diverse nervous system dysfunctions and even influence host behaviour to their own advantage. This Review discusses routes by which microbes can reach the nervous system and cause persistent or life-threatening infections.

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Figure 1: Nervous system entry sites for microbes.
Figure 2: White blood cells as carriers of microbes.
Figure 3: Axon-terminal uptake and transport of pathogens.
Figure 4: Olfactory route of neuroinvasion.
Figure 5: Non-cytolytic control of viral replication.

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Acknowledgements

The studies have been supported by grants from the Swedish Research Council (04480), European Commission (222887) and the US National Institutes of Health/Fogarty (5 R21 NS064888-02).

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Correspondence to Krister Kristensson.

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DATABASES

Pathway Interaction Database

Glossary

Neurovirulent

Refers to microbes that can replicate in the nervous system and cause functional disturbances.

Blood–brain barrier

A structure that protects the brain from non-selective passage of molecules and toxins in the blood while still allowing essential metabolites to cross. It is composed of tightly linked endothelial cells surrounded by astrocyte cell projections that are termed astrocytic endfeet.

Subarachnoid spaces

The space filled with cerebrospinal fluid between the arachnoid and the pia mater.

Tight junctions

Structures apposed to the plasma membrane of adjacent endothelial cells. They consist of a network of sealing strands that prevent passage of extracellular fluids; ZO1 is a tight junction protein that is often used as a marker.

Leptomeninges

The CNS is enclosed by three membranes — the outermost dura mater and the innermost pia mater with the arachnoid in between. The pia mater and the arachnoid are collectively called the leptomeninges.

Monocytes

Mononuclear cells that are derived from the bone marrow and circulate in the bloodstream. They pass into the body tissues, where they can differentiate into various types of macrophages.

Perivascular cuffs

Areas surrounding an inflamed blood vessel that contain inflammatory lymphocytes and are delimited by endothelial basement membrane on one side and parenchymal basement membrane on the other side.

Neurovascular units

Microdomains in the brain formed by astrocytes that integrate neural circuitry with local blood flow. Astrocytic processes form a bridge between cerebral vessels and synapses, and both are covered by astrocytic membranes.

Seizures

Transient abnormal, excessive or synchronous neuronal activity in the brain with clinical manifestations ranging from tonic spasm and clonic contractions of the muscles and convulsions to brief loss of awareness or psychic symptoms. Epilepsy signifies recurrent unprovoked seizures.

Circumventricular organs

Except for area portrema in the fourth ventricle, these organs are all located along the wall of the third ventricle and include the subfornicular organ, the laminar terminalis, the subcommisural organ, the median eminence and the neurohypophysis. They have fenestrated, leaky vessels whereby, for instance, axons projecting from hypothalamic neurons can secrete products into the bloodstream, but they can also serve as chemoreceptors to regulate homeostatic functions.

Perineurium

Layers of flattened cells that enclose fascicles of peripheral nerve fibres. The cells are joined by tight junctions, which prevent the diffusion of macromolecules into the enclosed nerve fibres.

Endoneural vessels

Vessels within the endoneurium (all connective tissue elements and spaces enclosed by the perineurium) that have tight junctions between adjacent endothelial cells to prevent the diffusion of macromolecules from the blood into the endoneural spaces.

Capsids

(From the Latin capsa, meaning box.) Protein shells that directly package viral DNA or RNA. The term nucleocapsid is sometimes used to describe the shell and its nucleic acid content.

Peripheral ganglia

Ganglia of nerve cell bodies in the peripheral nervous system encompassing dorsal root ganglia and cranial ganglia of the somatic division as well as ganglia of the autonomic division.

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Kristensson, K. Microbes' roadmap to neurons. Nat Rev Neurosci 12, 345–357 (2011). https://doi.org/10.1038/nrn3029

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