Mechanisms of Varicella-Zoster Virus Neuropathogenesis in Human Dorsal Root Ganglia

Reichelt, Mike; Zerboni, Leigh; Arvin, Ann M.

doi:10.1128/jvi.02592-07

Cited by 116 publications

(126 citation statements)

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“…VZV is a valuable model pathogen for investigating this process because natural infection of the human host involves formation of multinucleated polykaryocytes in skin and fusion of neurons and satellite cells in sensory ganglia (2, 6). In addition, VZV produces syncytia during replication in vitro and triggers fusion between differentiated cells in human skin and dorsal root ganglion xenografts infected in vivo in the severe combined immunodeficiency mouse model of VZV pathogenesis (7,8).Herpesvirus fusion is governed by a core complex of virion proteins consisting of the type I membrane glycoprotein B (gB) and the gH-gL heterodimer (9). We have recently shown that this core complex in VZV is sufficient to cause cell-cell fusion in the absence of other viral proteins (10).…”

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confidence: 99%

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An immunoreceptor tyrosine-based inhibition motif in varicella-zoster virus glycoprotein B regulates cell fusion and skin pathogenesis

Oliver¹,

Brady

Sommer³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Herpesvirus entry functions of the conserved glycoproteins gB and gH-gL have been delineated, but their role in regulating cell-cell fusion is poorly understood. Varicella-zoster virus (VZV) infection provides a valuable model for investigating cell-cell fusion because of the importance of this process for pathogenesis in human skin and sensory ganglia. The present study identifies a canonical immunoreceptor tyrosine-based inhibition motif (ITIM) in the gB cytoplasmic domain (gBcyt) and demonstrates that the gBcyt is a tyrosine kinase substrate. Orbitrap mass spectrometry confirmed that Y881, central to the ITIM, is phosphorylated. To determine whether the gBcyt ITIM regulates gB/gH-gL-induced cell-cell fusion in vitro, tyrosine residues Y881 and Y920 in the gBcyt were substituted with phenylalanine separately or together. Recombinant viruses with these substitutions were generated to establish their effects on syncytia formation in replication in vitro and in the human skin xenograft model of VZV pathogenesis. The Y881F substitution caused significantly increased cell-cell fusion despite reduced cell-surface gB. Importantly, the Y881F or Y881/920F substitutions in VZV caused aggressive syncytia formation, reducing cell-cell spread. These in vitro effects of aggressive syncytia formation translated to severely impaired skin infection in vivo. In contrast, the Y920F substitution did not affect virus replication in vitro or in vivo. These observations suggest that gB modulates cell-cell fusion via an ITIM-mediated Y881 phosphorylation-dependent mechanism, supporting a unique concept that intracellular signaling through this gBcyt motif regulates VZV syncytia formation and is essential for skin pathogenesis.fusogenicity | mutagenesis | polykaryocyte | virulence T he alphaherpesvirus varicella-zoster virus (VZV) is a human pathogen that spreads from mucosal epithelial sites of initial infection to skin via a T cell-associated viremia (1), causing varicella (chicken pox). Viremia and cutaneous infection enable transfer of VZV to sensory nerve ganglia and establishment of latency in neurons (2). Zoster (shingles) is caused by VZV reactivation from latently infected neurons and can lead to the debilitating condition of postherpetic neuralgia. Live attenuated VZV vaccines are effective against varicella and zoster but are not recommended for immunocompromised patients.Enveloped viruses from several families, including the Herpesviridae, require fusion with cellular membranes for virion entry, and in some cases induce syncytia through cell-cell fusion (2-5). Little is known about the functional role of syncytia during pathogenesis. VZV is a valuable model pathogen for investigating this process because natural infection of the human host involves formation of multinucleated polykaryocytes in skin and fusion of neurons and satellite cells in sensory ganglia (2, 6). In addition, VZV produces syncytia during replication in vitro and triggers fusion between differentiated cells in human skin and dorsal root ganglion xenograf...

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confidence: 99%

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confidence: 99%

An immunoreceptor tyrosine-based inhibition motif in varicella-zoster virus glycoprotein B regulates cell fusion and skin pathogenesis

Oliver¹,

Brady

Sommer³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…6A). Discontinuous NCAM staining was predominately observed when VZV gE-positive neurons were adjacent to infected satellite cells, as has been previously reported (11,27). Neurons infected with rOka⌬gI, however, showed a reduced alteration in NCAM localization and intensity compared with neurons infected with rOka, with only 20% of cells exhibiting aberrant NCAM staining (Fig.…”

Section: Fig 3 Assessment Of Viral Capsid and Glycoprotein Localizatimentioning

confidence: 47%

Varicella-Zoster Virus Glycoprotein I Is Essential for Spread in Dorsal Root Ganglia and Facilitates Axonal Localization of Structural Virion Components in Neuronal Cultures

Christensen

Steain

Slobedman

et al. 2013

J Virol

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bNeurons of the sensory ganglia are the major site of varicella-zoster virus (VZV) latency and may undergo productive infection during reactivation. Although the VZV glycoprotein E/glycoprotein I (gE/gI) complex is known to be critical for neurovirulence, few studies have assessed the roles of these proteins during infection of dorsal root ganglia (DRG) due to the high human specificity of the virus. Here, we show that the VZV glycoprotein I gene is an important neurotropic gene responsible for mediating the spread of virus in neuronal cultures and explanted DRG. Inoculation of differentiated SH-SY5Y neuronal cell cultures with a VZV gI gene deletion strain (VZV rOka⌬gI) showed a large reduction in the percentage of cells infected and significantly smaller plaque sizes in a comparison with cultures infected with the parental strain (VZV rOka). In contrast, VZV rOka⌬gI was not significantly attenuated in fibroblast cultures, demonstrating a cell type-specific role for VZV gI. Analysis of rOka⌬gI protein localization by immunofluorescent staining revealed aberrant localization of viral glycoprotein and capsid proteins, with little or no staining present in the axons of differentiated SH-SY5Y cells infected with rOka⌬gI, yet axonal vesicle trafficking was not impaired. Further studies utilizing explanted human DRG indicated that VZV gI is required for the spread of virus within DRG. These data demonstrate a role for VZV gI in the cell-to-cell spread of virus during productive replication in neuronal cells and a role in facilitating the access of virion components to axons. V aricella-zoster virus (VZV) is the etiological agent of the human disease varicella (chickenpox) (1). Following primary infection, the virus establishes latency within neurons of the sensory ganglia (2, 3), from where it may reactivate to result in the secondary clinical disease herpes zoster (shingles) (4). Herpes zoster may be followed by a state of debilitating, long-term pain known as postherpetic neuralgia (PHN), which is commonly resistant to many traditional pain therapies (3,5,6).VZV glycoprotein I (gI) is a type I membrane protein encoded by open reading frame 67 (ORF67) and functions primarily as a heterodimer with the most abundant VZV protein, gE (7). Although gI is dispensable in cell culture, deletion of the gene results in an impairment of syncytium formation, delayed replication, and a decrease in infectious virus yields within melanoma cells (8).In the context of neuronal infection, gI has been shown to be dispensable in a rat model of persistent VZV infection, although this host is nonpermissive (9). In a severe combined-immunodeficiency human (SCIDhu) mouse model of VZV infection utilizing human-xenografted dorsal root ganglia (DRG), infection with a VZV mutant lacking the gI gene (rOka⌬gI) resulted in prolonged replication within the DRG and an inability to transition to a persistent state, normally characterized by limited viral transcription (10). In addition, mutation of the cysteine-rich region in VZV gE responsible for ...

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“…Reichelt et al 84 used human DRG xenografts in the SCID-hu mouse to reveal VZV replication. Viral genomic DNA was present, and viral proteins IE62, IE63, and the early ORF47 kinase were expressed in the majority of neurons and satellite cells in VZV-infected DRG xenograft.…”

Section: Preclinical Evaluationsmentioning

confidence: 99%

“…Viral genomic DNA was present, and viral proteins IE62, IE63, and the early ORF47 kinase were expressed in the majority of neurons and satellite cells in VZV-infected DRG xenograft. 84 The first event in VZV reactivation from latency is thought to be polykaryon formation between a single neuron and adjacent satellite cells, allowing VZV virions released from satellite cells to infect nearby satellite cells that surround other neuronal cell bodies. 84 Use of autopsy DRG from HZ patients could identify the role of this satellite cell infection in the clinic, perhaps leading to possible avenues of therapeutic intervention.…”

Section: Preclinical Evaluationsmentioning

confidence: 99%

Postherpetic Neuralgia: From Preclinical Models to the Clinic

et al. 2009

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Summary: Postherpetic neuralgia (PHN), a common complication of herpes zoster, which results from reactivation of varicella zoster virus, is a challenging neuropathic pain syndrome. The incidence and severity of herpes zoster and PHN increases with immune impairment or age and may become a greater burden both in terms of health economics and individual suffering. A clearer understanding of the underlying mechanisms of this disease and translation of preclinical outcomes to the clinic may lead to more efficacious treatment options. Here we give an overview of recent findings from preclinical models and clinical research on PHN.

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Mechanisms of Varicella-Zoster Virus Neuropathogenesis in Human Dorsal Root Ganglia

Cited by 116 publications

References 32 publications

An immunoreceptor tyrosine-based inhibition motif in varicella-zoster virus glycoprotein B regulates cell fusion and skin pathogenesis

An immunoreceptor tyrosine-based inhibition motif in varicella-zoster virus glycoprotein B regulates cell fusion and skin pathogenesis

Varicella-Zoster Virus Glycoprotein I Is Essential for Spread in Dorsal Root Ganglia and Facilitates Axonal Localization of Structural Virion Components in Neuronal Cultures

Postherpetic Neuralgia: From Preclinical Models to the Clinic

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