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  • Review Article
  • Published:

Illuminating viral infections in the nervous system

Nature Reviews Immunology volume 11, pages 318–329 (2011)Cite this article

Subjects

Key Points

  • Specialized endothelial cells in the central nervous system (CNS) limit cellular and ionic movement into the brain parenchyma and act as a critical component of the blood–cerebral spinal fluid and blood–brain barriers. In certain anatomical locations, macrophages, microglia and astrocytes are juxtaposed to CNS blood vessels, and this positions these cells to present foreign antigens and/or provide additional barrier support. Innate immune cells such as macrophages and dendritic cells are also found in the meninges and choroid plexus, enabling surveillance of fluid spaces.

  • Viruses use several different strategies to bypass protective barriers and access the CNS. These strategies include haematological entry mechanisms, such as direct infection of vascular endothelium or travelling in immune cells across CNS barriers through a 'Trojan horse' mechanism. Viruses can also access peripheral nerves that reside outside the protective CNS barriers.

  • Immune responses to neurotropic viruses can promote viral clearance or latency, but sometimes give rise to pathology and disease. HIV persists in CNS myeloid cells (macrophages and microglia), giving rise to chronic innate and adaptive immune responses. This pro-inflammatory milieu can eventually cause neuronal damage and dementia. By contrast, herpes simplex virus latency in sensory ganglion neurons is maintained without injury, in part by innate cytokines and virus-specific T cells.

  • Two-photon laser scanning microscopy (TPLSM) is a microscopic technique that can be used to monitor the dynamics of immune responses to neurotropic viruses in real time. When conducting TPLSM experiments, the tissue preparation must be carefully considered because certain preparations can give rise to injury responses that confound data interpretation. Craniotomies and acute brain slices induce considerable tissue damage, whereas skull thinning opens a window for TPLSM imaging without brain injury.

  • Intravital TPLSM imaging of innate immune sentinels, such as dendritic cells, macrophages and microglia, can provide novel insights into their function within the normal and inflamed brain. Studies have revealed that microglia, for example, are highly dynamic under steady-state conditions and rapidly redirect their cellular processes to engulf debris following tissue injury.

  • Intravital imaging of CNS-infiltrating leukocytes during fatal viral meningitis has revealed that recruitment of myelomonocytic cells by virus-specific cytotoxic lymphocytes causes severe vascular injury and the rapid onset of convulsive seizures. Future imaging studies of CNS inflammatory responses following viral infection are required to determine how the immune system operates during states of viral clearance, latency and persistence.

Abstract

Viral infections are a major cause of human disease. Although most viruses replicate in peripheral tissues, some have developed unique strategies to move into the nervous system, where they establish acute or persistent infections. Viral infections in the central nervous system (CNS) can alter homeostasis, induce neurological dysfunction and result in serious, potentially life-threatening inflammatory diseases. This Review focuses on the strategies used by neurotropic viruses to cross the barrier systems of the CNS and on how the immune system detects and responds to viral infections in the CNS. A special emphasis is placed on immune surveillance of persistent and latent viral infections and on recent insights gained from imaging both protective and pathogenic antiviral immune responses.

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Figure 1: Anatomy of the brain.
Figure 2: CNS viral entry and spread.
Figure 3: Imaging antiviral immune responses in the brain.
Figure 4: Viral meningitis in real time.

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Acknowledgements

This work was supported by the National Institutes of Health (NIH) intramural program. S.S.K. is presently supported by a NIH National Research Service Award (NS061447-01). We would like to thank J. Kim and M. Dustin at New York University for insightful discussions and a very supportive collaboration focused on imaging CNS antiviral immunity.

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Authors and Affiliations

  1. National Institute of Neurological Disorders and Stroke, The National Institutes of Health, Bethesda, 20892, Maryland, USA

    Dorian B. McGavern & Silvia S. Kang

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  1. Dorian B. McGavern
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Correspondence to Dorian B. McGavern.

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Supplementary information

Supplementary information S1 (Movie)

CNS immune sentinels. (MOV 37922 kb)

41577_2011_BFnri2971_MOESM4_ESM.pdf

Supplementary information S2 (Movie)

3D projections of the meninges, glial limitans and BBB. (MOV 24025 kb)

41577_2011_BFnri2971_MOESM6_ESM.pdf

Supplementary information S3 (Movie)

Distribution of LCMV in meningeal stroma. (MOV 9580 kb)

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Supplementary information S4 (Movie)

Viral meningitis in 4D. (MOV 27455 kb)

41577_2011_BFnri2971_MOESM10_ESM.pdf

Supplementary information S5 (Movie)

Vascular occlusion and breakdown during LCMV meningitis. (MOV 8191 kb)

41577_2011_BFnri2971_MOESM12_ESM.pdf

Glossary

Immune-privileged

A term used to describe areas of the body with a decreased inflammatory response to foreign antigens, including tissue grafts. These sites include the brain, eye, testis and placenta.

Blood–brain barrier

A barrier formed by tight junctions between endothelial cells that markedly limits entry to the CNS by leukocytes and all large molecules, including to some extent immunoglobulins, cytokines and complement proteins.

Meninges

The membranes surrounding the brain and spinal cord. There are three layers of meninges: the dura mater (outer), the arachnoid mater (middle) and the pia mater (inner).

Aseptic meningitis

Infection and inflammation of the meninges that is not caused by bacteria. Enteroviruses such as echovirus and coxsackie virus are the most common cause of viral meningitis, but cytomegalovirus, HSV, HIV, JEV, LCMV, mumps virus, rabies virus, VZV and WNV can also cause the disease.

Encephalitis

Infection and inflammation of the brain parenchyma. This can be caused by adenovirus, cytomegalovirus, coxsackievirus, EBV, echovirus, HSV, measles virus, poliovirus, mumps virus, rabies virus, rubella virus, VZV and WNV.

Meningoencephalitis

A disease that resembles both meningitis and encephalitis and is characterized by infection and inflammation of both the meninges and brain parenchyma.

Two-photon laser scanning microscopy

(TPLSM). Laser scanning microscopy that uses pulsed infrared laser light for the excitation of conventional fluorophores or fluorescent proteins. This technique greatly reduces photodamage to living specimens and improves the depth of tissue penetration, owing to the low level of light scattering within the tissue.

Tight junctions

A belt-like region of adhesion between adjacent epithelial or endothelial cells that regulates paracellular flux. Tight-junction proteins include the integral membrane proteins occludin and claudin, in association with cytoplasmic zonula occludins proteins.

Pericytes

Cells embedded in the vascular basement membrane of microvessels that are thought to be derived from the vascular smooth muscle lineage. They make close cellular contact with endothelial cells and this interaction is essential for the maintenance of vessel function, as well as for the regulation of angiogenesis and vascular remodelling.

Anterograde and retrograde transport systems

Cargo is moved between the cell body (soma) and the synapse of neurons using two transport mechanisms. The anterograde transport system uses kinesin motors to move cargo from the cell body to the synapse, whereas the retrograde system moves material from the synapse back to the cell body using dynein.

Antigenic drift

A process by which circulating influenza viruses are constantly changing, which allows the virus to cause annual epidemics of illness. Antigenic drift occurs when mutations accumulate in the haemagglutinin and neuraminidase genes and alter the antigenicity of these proteins such that the 'drifted' strains are no longer neutralized by antibodies that were specific for previously circulating strains.

Pathogen-associated molecular patterns

(PAMPs). Molecular patterns that are found in pathogens but not in mammalian cells. Examples include terminally mannosylated and polymannosylated compounds (which bind the mannose receptor) and various microbial components, such as bacterial lipopolysaccharide, hypomethylated DNA, flagellin and double-stranded RNA (all of which bind Toll-like receptors).

γδ T cells

T cells that express the γδ T cell receptor. These T cells are present in the skin, vagina and intestinal epithelium as intraepithelial lymphocytes.

MicroRNAs

(miRNAs). Small RNA molecules that regulate the expression of genes by binding to the 3′-untranslated regions (3′-UTRs) of specific mRNAs.

Quantum dot

A nanocrystalline semiconductor of extremely small size (5–50 nm in diameter) that absorbs incident photons and then emits light of a slightly longer wavelength. Because of a phenomenon called the quantum confinement effect, the colour (wavelength) of the emitted light is determined by the size of the nanocrystal.

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McGavern, D., Kang, S. Illuminating viral infections in the nervous system. Nat Rev Immunol 11, 318–329 (2011). https://doi.org/10.1038/nri2971

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