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Review
. 2016 Dec;17(12):766-776.
doi: 10.1038/nrn.2016.140. Epub 2016 Nov 4.

Keeping it in check: chronic viral infection and antiviral immunity in the brain

Katelyn D Miller  1   2 , Matthias J Schnell  3 , Glenn F Rall  2
Affiliations
Review

Keeping it in check: chronic viral infection and antiviral immunity in the brain

Katelyn D Miller et al. Nat Rev Neurosci. 2016 Dec.

Abstract

It is becoming clear that the manner by which the immune response resolves or contains infection by a pathogen varies according to the tissue that is affected. Unlike many peripheral cell types, CNS neurons are generally non-renewable. Thus, the cytolytic and inflammatory strategies that are effective in controlling infections in the periphery could be damaging if deployed in the CNS. Perhaps for this reason, the immune response to some CNS viral infections favours maintenance of neuronal integrity and non-neurolytic viral control. This modified immune response - when combined with the unique anatomy and physiology of the CNS - provides an ideal environment for the maintenance of viral genomes, including those of RNA viruses. Therefore, it is possible that such viruses can reactivate long after initial viral exposure, contributing to CNS disease.

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Conflict of interest statement

Competing interests statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1. Viral entry into the CNS
Three modes of viral entry into the brain are shown. a | Viruses may directly infect the cells comprising the blood–brain barrier (BBB), followed by release into the parenchymal space (left panel). Alternatively, viruses may diffuse across permeable regions of the BBB (middle panel). Of note, BBB permeability can be influenced by cytokines, such as tumour necrosis factor (TNF) and various interferons (IFNβ, IFNγ and IFNλ), which can loosen or reinforce the barrier integrity. In the ‘Trojan horse’ approach (right panel), infected lymphocytes or monocytes (including macrophages) traffic across the BBB or blood–cerebrospinal fluid barrier, releasing the virus once in the brain parenchyma. b | Trans-synaptic spread of viral particles involves the transport of viral genomes and associated proteins via microtubules and molecular motors. The left panel shows the movement of rabies virus (RABV) from the muscle, across the neuromuscular junction, and the dynein-mediated retrograde transport of this virus into the CNS. In the right panel, the transport of viruses (including herpes simplex virus (HSV), varicella zoster virus (VZV) and pseudorabies virus (PRV)) occurs across the epithelial or endothelial–neuron junction. In these neurons, retrograde transport brings the virus to the neuronal soma, and anterograde transport delivers the virus to the peripheral nervous system (PNS)–CNS synaptic junction. IFNAR, IFN α/β receptor; IFNGR, IFNγ receptor; HIV-1, human immunodeficiency virus type 1; MV, measles virus; PV, poliovirus; TNFR, TNF receptor; WNV, West Nile virus. Part a is adapted with permission from REF., PLoS. Part b is adapted with permission from REF., Elsevier.
Figure 2
Figure 2. The receptor-occupancy hypothesis
In cells with abundant levels of signal transducer and activator of transcription 1 (STAT1) signalling proteins, engagement of the interferon-γ (IFNγ) receptor (IFNGR) by its ligand transduces a primarily STAT1-driven cellular response, leading to activation of gene products that are chiefly antiviral (part a). By contrast, when a particular cell population (such as hippocampal neurons) expresses reduced homeostatic levels of STAT1 (part b) or when STAT1 is removed by genetic deletion (part c), alternative signalling molecules with an affinity to the IFNGR may bind to this receptor, transducing unique cellular responses. In the case of neurons, this includes activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), which then can result in the induction of genes encoding pro-survival proteins. JAK1, Janus kinase 1; KO, knockout; MEF, mouse embryonic fibroblast.
Figure 3
Figure 3. Tropism of neurotropic RNA viruses for distinct brain regions and neuronal subpopulations
The schematics show a simplified sagittal view of the mouse brain with the regions that are known to be infected by various viruses indicated in red. The symbol ‘>‘ indicates higher propensity for a virus to infect a certain cell type or region of the brain than another cell type or region. MHV, mouse hepatitis virus; MV, measles virus; RABV, rabies virus; WNV, West Nile virus.
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References

    1. Paludan SR, Bowie AG, Horan KA, Fitzgerald KA. Recognition of herpesviruses by the innate immune system. Nat Rev Immunol. 2011;11:143–154. - PMC - PubMed
    1. Jones CA, et al. Herpes simplex virus type 2 induces rapid cell death and functional impairment of murine dendritic cells in vitro. J Virol. 2003;77:11139–11149. - PMC - PubMed
    1. Braaten DC, Sparks-Thissen RL, Kreher S, Speck SH, Virgin HW. An optimized CD8+ T-cell response controls productive and latent gammaherpesvirus infection. J Virol. 2005;79:2573–2583. - PMC - PubMed
    1. Koyuncu OO, Hogue IB, Enquist LW. Virus infections in the nervous system. Cell Host Microbe. 2013;13:379–393. - PMC - PubMed
    1. Dittmar S, et al. Measles virus-induced block of transendothelial migration of T lymphocytes and infection-mediated virus spread across endothelial cell barriers. J Virol. 2008;82:11273–11282. - PMC - PubMed

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