Immune responses to West Nile virus infection in the central nervous system - PubMed (original) (raw)

Review

Immune responses to West Nile virus infection in the central nervous system

Hyelim Cho et al. Viruses. 2012.

Abstract

West Nile virus (WNV) continues to cause outbreaks of severe neuroinvasive disease in humans and other vertebrate animals in the United States, Europe, and other regions of the world. This review discusses our understanding of the interactions between virus and host that occur in the central nervous system (CNS), the outcome of which can be protection, viral pathogenesis, or immunopathogenesis. We will focus on defining the current state of knowledge of WNV entry, tropism, and host immune response in the CNS, all of which affect the balance between injury and successful clearance.

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Figures

Figure 1

Figure 1

Mechanism of neuroinvasion of West Nile virus (WNV). WNV may enter the central nervous system (CNS) via multiple mechanisms including axonal retrograde transport along peripheral neurons into the spinal cord or hematogenous transport across the blood-brain barrier (BBB). Spinal cord entry is believed to result in interneuron spread to motor neuron cell bodies within the anterior horn of the spinal cord and lead to flaccid paralysis. The possible routes of virus entry across the BBB include (a) “Trojan horse” model; intracellular transport within macrophages or neutrophils, (b) loss of integrity of the BBB; cytokine-mediated (TNF-α, MIF) or matrix metalloproteinases disruption of tight junctions and basement membranes; (c) direct infection of brain microvascular endothelial cells with basolateral spread of the virus; (d) infection of choroid plexus epithelial cells; or (e) direct infection of olfactory neurons adjacent to the cribriform plate.

Figure 2

Figure 2

Leukocyte trafficking into the CNS after WNV. Upon WNV infection of neurons, virus-mediated upregulation of Cxcl10 recruits virus-specific CD8+ T cells via interactions with Cxcr3. Expression of Ccl3, Ccl4, and Ccl5 by other neuronal cells recruits Ccr5-expressing leukocytes. Monocytes and lymphocytes entering the perivascular spaces may be retained initially via Cxcr4 binding Cxcl12 [120]. Leukocyte egress from perivascular spaces requires IL-1β, TNF-α, and CD40 interactions, which likely upregulates adhesion molecules including ICAM-1 and VCAM-1 [121,123,124].

Figure 3

Figure 3

Mechanisms of CD8+ T cell clearance in the CNS. CD8+ T cells control WNV infection in the CNS through multiple mechanisms. Infected neurons upregulate surface expression of MHC class I molecules. Antigen-specific CD8+ T cells recognize infected neurons via class I MHC and processed viral peptides and trigger cell death of target cells through perforin, Fas-Fas ligand, or TRAIL-dependent pathways. Perforin-mediated control of infected neurons occurs through the granzyme-dependent granule exocytosis pathway, which results in apoptosis of infected neuron. Interactions between Fas on infected neurons and FasL on CD8+ T cells leads to programmed cell death of neurons through caspase-dependent pathways. CD8+ T cells also utilize TRAIL to restrict WNV infection in neurons. TRAIL binds to DR5 on neurons, which can have a direct antiviral effect against flaviviruses [125] or result in targeted apoptosis. Activated CD8+ T cell also produce IFN-γ, which can induce genes with antiviral effect.

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