Experimental Models to Study Varicella-Zoster Virus Infection of Neurons

Steain, Megan; Slobedman, Barry; Abendroth, Allison

doi:10.1007/82_2010_15

Cited by 16 publications

(11 citation statements)

References 84 publications

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“…Thus, VZV gene silencing in neurons is a cell type-specific characteristic of the VZV–host interaction. Infection of explanted foetal DRG neurons in vitro showed that IE63 has anti-apoptotic functions that might facilitate this transition 88,89 .…”

Section: Neurotropismmentioning

confidence: 99%

Molecular mechanisms of varicella zoster virus pathogenesis

et al. 2014

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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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Section: Neurotropismmentioning

confidence: 99%

Molecular mechanisms of varicella zoster virus pathogenesis

et al. 2014

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“…The model also revealed roles for innate responses in virus control in skin (Ku et al 2005). SCID-hu mice with human ganglionic/neurological tissue (Zerboni et al 2010a), coupled with ex vivo culture models such as human fetal ganglia explants and model neuronal cultures (Christensen et al 2011; Gowrishankar et al 2007; Steain et al 2010; Markus et al 2011; Pugazhenthi et al 2011), will likely shed light on aspects of the VZV latent state and VZV neurotropism. However, the assessment of pain is a conscious response that requires functioning in vivo models with intact sensory enervation of both peripheral and central systems.…”

Section: The Rodent Model Of Vzv-induced Painmentioning

confidence: 99%

Varicella zoster virus-induced pain and post-herpetic neuralgia in the human host and in rodent animal models

Kinchington

Goins

2011

J. Neurovirol.

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Pain and post-herpetic neuralgia (PHN) are common and highly distressing complications of herpes zoster that remain a significant public health concern and in need of improved therapies. Zoster results from reactivation of the herpesvirus varicella zoster virus (VZV) from a neuronal latent state established at the primary infection (varicella). PHN occurs in some one fifth to one third of zoster cases with severity, incidence, and duration of pain increasing with rising patient age. While VZV reactivation and the ensuing ganglionic damage trigger the pain response, the mechanisms underlying protracted PHN are not understood, and the lack of an animal model of herpes zoster (reactivation) makes this issue more challenging. A recent preclinical rodent model has developed that opens up the potential to allow the exploration of the underlying mechanisms and treatments for VZV-induced pain. Rats inoculated with live cell-associated human VZV into the hind paw reliably demonstrate thermal hyperalgesia and mechanical allodynia for extended periods and then spontaneously recover. Dorsal root ganglia express a limited VZV gene subset, including the IE62 regulatory protein, and upregulate expression of markers suggesting a neuropathic pain state. The model has been used to investigate treatment modalities and aspects of pain signaling and is under investigation by the authors to delineate VZV genetics involved in the induction of pain. This article compares human zoster-associated pain and PHN to the pain indicators in the rat and poses important questions that, if answered, could be the basis for new treatments.

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“…Neuronal infection becomes persistent through the establishment of latency, and subsequent reactivation usually leads to anterograde axonal transport to the periphery and the formation of lesions typical of herpes zoster (shingles), usually in older or immunocompromised persons. Unlike the related alphaherpesviruses pseudorabies virus (PrV) and herpes simplex viruses (HSV) whose wider host range has facilitated study in animal systems, VZV is highly human-tropic: infection of most animal neurons does not result to a full productive infection (Steain et al 2010). There have been a few studies of VZV infection of isolated human fetal dorsal root ganglion (DRG) neurons; however, the limited accessibility to this material has resulted in the direct demonstration of axonal transport and retrograde infection of neurons by VZV being performed only very recently by our groups (Markus et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Retrograde axonal transport of VZV: kinetic studies in hESC-derived neurons

et al. 2012

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Retrograde axonal transport of the neurotropic alphaherpesvirus Varicella zoster virus (VZV) from vesicles at the skin results in sensory neuron infection and establishment of latency. Reactivation from latency leads to painful herpes zoster. The lack of a suitable animal model of these processes for the highly human-restricted VZV has resulted in a dearth of knowledge regarding the axonal transport of VZV. We recently demonstrated VZV infection of distal axons, leading to subsequent capsid transport to the neuronal somata, and replication and release of infectious virus using a new model based on neurons derived from human embryonic stem cells (hESC). In the present study, we perform a kinetic analysis of the retrograde transport of green fluorescent protein-tagged ORF23 in VZV capsids using hESC-derived neurons compartmentalized microfluidic chambers and time-lapse video microscopy. The motion of the VZV was discontinuous, showing net retrograde movement with numerous short pauses and reversals in direction. Velocities measured were higher 1 h after infection than 6 h after infection, while run lengths were similar at both time points. The hESC-derived neuron model was also used to show that reduced neuronal spread by a VZV loss-of-function mutant for ORF7 is not due to the prevention of axonal infection and transport of the virus to the neuronal somata. hESC-derived neurons are, therefore, a powerful model for studying axonal transport of VZV and molecular characteristics of neuronal infection.

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Experimental Models to Study Varicella-Zoster Virus Infection of Neurons

Cited by 16 publications

References 84 publications

Molecular mechanisms of varicella zoster virus pathogenesis

Molecular mechanisms of varicella zoster virus pathogenesis

Varicella zoster virus-induced pain and post-herpetic neuralgia in the human host and in rodent animal models

Retrograde axonal transport of VZV: kinetic studies in hESC-derived neurons

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