Promoter Sequences of Varicella-Zoster Virus Glycoprotein I Targeted by Cellular Transactivating Factors Sp1 and USF Determine Virulence in Skin and T Cells in SCIDhu Mice In Vivo

Ito, Hideki; Sommer, Marvin; Zerboni, Leigh; He, Haiyang; Boucaud, Dwayne; Hay, John; Ruyechan, William T.; Arvin, Ann M.

doi:10.1128/jvi.77.1.489-498.2003

Cited by 52 publications

(68 citation statements)

References 43 publications

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“…These experiments demonstrated that VZV spreads efficiently between neural cells in vivo, without changing cellular morphology or expression of neural cell proteins, including hNCAM, hGFAP, and ␤-tubulin III. VZV gene expression in neural cells differed dramatically from VZV infection of epidermal and dermal cells in human skin in vivo, which is associated with cell destruction and release of infectious virions (20)(21)(22)(23)(24). IE62, the major viral transactivating protein and an important component of the virion tegument (38,39), was restricted to the nuclei of neurons and glial cells, whereas IE62 localized to the cytoplasm of infected skin cells.…”

Section: Discussionmentioning

confidence: 98%

“…VZV causes lytic infection of human dermal and epidermal cells in skin xenografts in vivo (20)(21)(22)(23)(24)38). To compare VZV protein expression in human neural and skin cells in vivo, skin xenografts were collected 3 weeks after VZV infection, and alternate sections were examined for IE62, IE63, ORF47 kinase, or gE synthesis (Fig.…”

Section: Vzv Protein Expression In Infected Skinmentioning

confidence: 99%

“…The expanding populations migrate throughout the brain from the SVZ to the olfactory bulb, express human neuronal and glial cell markers, and develop axonal processes. Skin and thymus͞liver xenografts in SCID mice permit analysis of VZV tropism for human epidermal and dermal cells and T cells within their intact tissue microenvironments in vivo (20)(21)(22)(23)(24). Therefore, we used the chimeric NOD-SCID mouse-human neural cell model to investigate VZV infection of differentiated neural cells in vivo.…”

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confidence: 99%

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Varicella-zoster virus infection of human neural cells in vivo

Baiker

Fabel

Cozzio

et al. 2004

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

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Varicella-zoster virus (VZV) establishes latency in sensory ganglia and causes herpes zoster upon reactivation. These investigations in a nonobese diabetic severe combined immunodeficient mousehuman neural cell model showed that VZV infected both neurons and glial cells and spread efficiently from cell to cell in vivo. Neural cell morphology and protein synthesis were preserved, in contrast to destruction of epithelial cells by VZV. Expression of VZV genes in neural cells was characterized by nuclear retention of the major viral transactivating protein and a block in synthesis of the predominant envelope glycoprotein. The attenuated VZV vaccine strain retained infectivity for neurons and glial cells in vivo. VZV gene expression in differentiated human neural cells in vivo differs from neural infection by herpes simplex virus, which is characterized by latency-associated transcripts, and from lytic VZV replication in skin. The chimeric nonobese diabetic severe combined immunodeficient mouse model may be useful for investigating other neurotropic human viruses.

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Section: Discussionmentioning

confidence: 98%

Section: Vzv Protein Expression In Infected Skinmentioning

confidence: 99%

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confidence: 99%

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Varicella-zoster virus infection of human neural cells in vivo

Baiker

Fabel

Cozzio

et al. 2004

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

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“…It is known that promoters of all kinetic classes of VZV genes contain cognate binding sites for a variety of cellular transcription factors, e.g. Oct-1, USF, Sp1, NF-kB and AP-1 (Ito et al, 2003;Kinchington et al, 1994;Meier et al, 1994;Rahaus & Wolff, 2000), which are all targets of upstream signalling pathways. Downregulation of the expression of AP-1 affects the efficiency of transactivation and effectiveness of replication .…”

Section: Discussionmentioning

confidence: 99%

Replication of varicella-zoster virus is influenced by the levels of JNK/SAPK and p38/MAPK activation

Rahaus

Desloges

Wolff

2004

Journal of General Virology

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Stimulation of the Jun NH 2 -terminal kinase/stress-activated protein kinase (JNK/SAPK) and the p38 mitogen-activated protein kinase (p38/MAPK) is part of the stress-related signal transduction pathways conveying signals from the cell surface into the nucleus in order to initiate programmes of gene expression. Here, it was shown that infection by varicella-zoster virus (VZV) caused a 34-fold increase in activation of JNK/SAPK in the early phase of infection and a 2-fold increase in activation of p38/MAPK in the later phase. The phosphorylation of downstream targets c-Jun and ATF-2 was also increased; subsequent cascades to induce pro-inflammatory responses were significantly activated whereas cascades to activate apoptotic events were not. In the late phase of infection, both JNK/SAPK and p38/MAPK activities were reduced to basal levels. The use of specific inhibitors demonstrated that inhibition of JNK/SAPK resulted in a 2-fold increase in VZV replication whereas a strong decrease in virus replication was observed after inhibition of p38/MAPK. In contrast, constitutive activation of JNK/SAPK resulted in a decline in VZV replication. Blocking gene expression by treating cells with actinomycin D or cycloheximide prior to infection resulted in activation of neither JNK/SAPK nor p38/MAPK. It was assumed that the presence of tegument proteins was not sufficient to activate stress pathways, but that expression of viral genes was necessary. This suggests that activation of stress pathways by VZV infection represents a finely regulated system that activates cellular transcription factors for transregulation of VZV-encoded genes, but prevents activation of cellular defence mechanisms.

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“…10B). Infectious rOKA/ ORF63rev[S185] was not recovered at 20 days, but this pattern was due to extensive infection and depletion of T cells, by immunohistochemistry analysis (data not shown); declining titers at days 21 to 28 days after T-cell infection with low passage clinical isolates or intact recombinants made from cosmids is characteristic of VZV replication in T-cell xenografts (3,13,32,40).…”

Section: Analysis Of Ie62/ie63 Binding In the Ie63 Mutant Virusesmentioning

confidence: 99%

The Immediate-Early 63 Protein of Varicella-Zoster Virus: Analysis of Functional Domains Required for Replication In Vitro and for T-Cell and Skin Tropism in the SCIDhu Model In Vivo

Baiker¹,

Bagowski²,

Ito³

et al. 2004

J Virol

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The immediate-early 63-kDa (IE63) protein of varicella-zoster virus (VZV) is a phosphoprotein encoded by open reading frame (ORF) ORF63/ORF70. To identify functional domains, 22 ORF63 mutations were evaluated for effects on IE63 binding to the major VZV transactivator, IE62, and on IE63 phosphorylation and nuclear localization in transient transfections, and after insertion into the viral genome with VZV cosmids. The IE62 binding site was mapped to IE63 amino acids 55 to 67, with R59/L60 being critical residues. Alanine substitutions within the IE63 center region showed that S165, S173, and S185 were phosphorylated by cellular kinases. Four mutations that changed two putative nuclear localization signal (NLS) sequences altered IE63 distribution to a cytoplasmic/nuclear pattern. Only three of 22 mutations in ORF63 were compatible with recovery of infectious VZV from our cosmids, but infectivity was restored by inserting intact ORF63 into each mutated cosmid. The viable IE63 mutants had a single alanine substitution, altering T171, S181, or S185. These mutants, rOKA/ORF63rev[T171], rOKA/ORF63rev[S181], and rOKA/ORF63rev[S185], produced less infectious virus and had a decreased plaque phenotype in vitro. ORF47 kinase protein and glycoprotein E (gE) synthesis was reduced, indicating that IE63 contributed to optimal expression of early and late gene products. The three IE63 mutants replicated in skin xenografts in the SCIDhu mouse model, but virulence was markedly attenuated. In contrast, infectivity in T-cell xenografts was not altered. Comparative analysis suggested that IE63 resembled the herpes simplex virus type 1 U S 1.5 protein, which is expressed colinearly with ICP22 (U S 1). In summary, most mutations of ORF63 made with our VZV cosmid system were lethal for infectivity. The few IE63 changes that were tolerated resulted in VZV mutants with an impaired capacity to replicate in vitro. However, the IE63 mutants were attenuated in skin but not T cells in vivo, indicating that the contribution of the IE63 tegument/regulatory protein to VZV pathogenesis depends upon the differentiated human cell type which is targeted for infection within the intact tissue microenvironment.Varicella-zoster virus (VZV), a member of the alphaherpesvirus subfamily of the Herpesviridae, causes varicella during primary infection and herpes zoster when it reactivates from latency in sensory ganglia. The VZV genome is a doublestranded DNA molecule of approximately 125 kb with open reading frames (ORFs) that are known or predicted to encode at least 70 distinct gene products (1). The genome consists of two main coding regions, the unique long (U L ) and unique short (U S ) regions, each of which is flanked by internal repeat (IR) and terminal repeat (TR) sequences. Three ORFs, including ORF63/70 as well as ORF62/71 and ORF64/69, are located within the repeat sequences and are therefore duplicated within the VZV genome (7).The development of VZV cosmid systems has permitted the functional analysis of VZV gene products by deleting ORFs or i...

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Promoter Sequences of Varicella-Zoster Virus Glycoprotein I Targeted by Cellular Transactivating Factors Sp1 and USF Determine Virulence in Skin and T Cells in SCIDhu Mice In Vivo

Abstract: Varicella-zoster virus (VZV) glycoprotein I is dispensable in cell culture but necessary for infection of human skin and T cells in

Cited by 52 publications

References 43 publications

Varicella-zoster virus infection of human neural cells in vivo

Varicella-zoster virus infection of human neural cells in vivo

Replication of varicella-zoster virus is influenced by the levels of JNK/SAPK and p38/MAPK activation

The Immediate-Early 63 Protein of Varicella-Zoster Virus: Analysis of Functional Domains Required for Replication In Vitro and for T-Cell and Skin Tropism in the SCIDhu Model In Vivo

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