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  • Review Article
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Molecular mechanisms of varicella zoster virus pathogenesis

Key Points

  • Varicella zoster virus (VZV) causes varicella and zoster. This herpesvirus is highly human-specific; therefore, human tissue xenografts in mice with severe combined immunodeficiency (SCID) provide an opportunity to define the molecular mechanisms of VZV pathogenesis and tissue tropism.

  • VZV-infected T cells transport the virus through the circulation, migrate into skin and initiate cutaneous lesion formation. T cells also deliver VZV to dorsal root ganglia (DRG), where latency is established.

  • VZV undergoes a transition to persistence in neurons within DRG xenografts, whereas progressive lytic infection occurs in skin and T cell xenografts, which indicates that VZV gene silencing is a neuron-specific characteristic.

  • Whereas many viral proteins are incidental for replication in vitro, specialized functions, complete VZV proteins and small motifs or single amino acids are often crucial in vivo and contribute to pathogenesis that varies depending on the target cell and tissue microenvironment. Cell transcription factors that synergistically control viral gene expression with viral regulatory proteins also have cell-type specific effects on VZV infection.

  • VZV pathogenesis depends on reprogramming cell signalling pathways within infected cells to support cell survival and disrupt innate antiviral defences. This enables infected T cells to reach skin and DRG, supports the formation of virus-filled lesions at the skin surface and facilitates the establishment of latency.

  • VZV is the only human herpesvirus for which a vaccine has been developed. Live attenuated VZV vaccines contain a mixture of VZV genomes that have varying polymorphisms. Mutations that are accumulated during tissue culture passage reduce the capacity to overcome the innate antiviral barriers in skin but do not affect VZV pathogenesis in T cells or DRG.

  • Virus–host interactions during VZV pathogenesis are modulated to avoid an overwhelming infection, which benefits the virus by ensuring that there are opportunities for transmission and persistence of this ubiquitous pathogen in the human population.

Abstract

Varicella zoster virus (VZV) is the causative agent of varicella (chickenpox) and zoster (shingles). Investigating VZV pathogenesis is challenging as VZV is a human-specific virus and infection does not occur, or is highly restricted, in other species. However, the use of human tissue xenografts in mice with severe combined immunodeficiency (SCID) enables the analysis of VZV infection in differentiated human cells in their typical tissue microenvironment. Xenografts of human skin, dorsal root ganglia or foetal thymus that contains T cells can be infected with mutant viruses or in the presence of inhibitors of viral or cellular functions to assess the molecular mechanisms of VZV–host interactions. In this Review, we discuss how these models have improved our understanding of VZV pathogenesis.

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Figure 1: VZV life cycle and replication.
Figure 2: VZV T cell tropism.
Figure 3: VZV skin tropism.
Figure 4: VZV neurotropism in DRG xenografts.

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Acknowledgements

The authors thank M. Sommer, X. Che, L. Wang and M. Reichelt, past postdoctoral fellows and students and collaborators and many dedicated colleagues in the field of VZV research for their invaluable contributions. J. Moffat initiated the development of the SCID mouse model as a postdoctoral fellow in the Arvin laboratory. This work is supported by US National Institutes of Health (NIH) grants, AI20459, AI05346 and AI102546.

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Correspondence to Ann M. Arvin.

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Glossary

Dermatome

An area of skin that is primarily innervated by a single sensory ganglion of the spinal cord.

Trans-Golgi network

(TGN). An intracellular collection of tubules and vesicles that are located at the trans face of the Golgi stack; it is involved in processing glycoproteins.

Syncytia

Multinucleated cells that are created by fusion of membranes between cells with single nuclei; multinucleated cells in tissue are referred to as polykaryocytes.

Polykaryocytes

Cells that contain many nuclei.

Xenografts

Tissues from one species that have been transplanted into a different species.

Severe combined immunodeficiency

(SCID). A genetic defect that blocks the function of T cells and B cells, interfering with the capacity of the host to mount an effective immune response to foreign proteins.

Dorsal root ganglia

(DRG). Nodules on the dorsal root of the spinal cord that contain sensory nerve cell bodies.

Anastomosis

The end-to-end connection of tubular structures, such as capillaries.

Waldeyer's ring

An annular arrangement of lymphoid tissue in the oropharynx; it consists of the pharyngeal, tubal, palatine and lingual tonsils.

Diapedesis

The passage of lymphocytes and cells of the immune system through intact vessel walls.

Major histocompatibility complex I

A protein that is present on the surfaces of most mammalian cells that functions to present peptide epitopes to T cells.

Satellite cells

Glial cells that surround the surfaces of neurons in the peripheral nervous system.

Neuropathic pain

Pain that is caused by damage to the somatosensory system; it is associated with increased sensitivity to touch, temperature and other stimuli.

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Zerboni, L., Sen, N., Oliver, S. et al. Molecular mechanisms of varicella zoster virus pathogenesis. Nat Rev Microbiol 12, 197–210 (2014). https://doi.org/10.1038/nrmicro3215

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