Impact of Varicella-Zoster Virus on Dendritic Cell Subsets in Human Skin during Natural Infection

Huch, Jennifer H.; Cunningham, Anthony L.; Arvin, Ann M.; Nasr, Najla; Santegoets, Saskia J.; Slobedman, Eric; Slobedman, Barry; Abendroth, Allison

doi:10.1128/jvi.01450-09

Cited by 62 publications

(72 citation statements)

References 65 publications

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“…The IHC staining pattern of the new ORF62-and ORF63-specific MAbs resembled that of the previously established ORF62 (clone 8616)-and ORF63 (clone 9D12)-specific MAbs (31, 37). As reported previously, positive staining of ORF4, ORF62, and ORF63 occurred in both the nuclei and cytoplasm of epidermal and infundibular keratinocytes (38,39). Overall, the data demonstrate the applicability of these MAbs for IHC purposes.…”

Section: Generation Of Monoclonal Antibodies Against Vzv Proteinssupporting

confidence: 86%

Comprehensive Analysis of Varicella-Zoster Virus Proteins Using a New Monoclonal Antibody Collection

Roviš

Bailer

Pothineni

et al. 2013

J Virol

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i Varicella-zoster virus (VZV) is the etiological agent of chickenpox and shingles. Due to the virus's restricted host and cell type tropism and the lack of tools for VZV proteomics, it is one of the least-characterized human herpesviruses. We generated 251 monoclonal antibodies (MAbs) against 59 of the 71 (83%) currently known unique VZV proteins to characterize VZV protein expression in vitro and in situ. Using this new set of MAbs, 44 viral proteins were detected by Western blotting (WB) and indirect immunofluorescence (IF); 13 were detected by WB only, and 2 were detected by IF only. A large proportion of viral proteins was analyzed for the first time in the context of virus infection. Our study revealed the subcellular localization of 46 proteins, 14 of which were analyzed in detail by confocal microscopy. Seven viral proteins were analyzed in time course experiments and showed a cascade-like temporal gene expression pattern similar to those of other herpesviruses. Furthermore, selected MAbs tested positive on human skin lesions by using immunohistochemistry, demonstrating the wide applicability of the MAb collection. Finally, a significant portion of the VZV-specific antibodies reacted with orthologs of simian varicella virus (SVV), thus enabling the systematic analysis of varicella in a nonhuman primate model system. In summary, this study provides insight into the potential function of numerous VZV proteins and novel tools to systematically study VZV and SVV pathogenesis. V aricella-zoster virus (VZV) belongs to the alphaherpesvirus subfamily and is the only member of the genus Varicellovirus that can infect humans (1, 2). Primary infection causes chickenpox and typically occurs in early childhood with a prominent, highly contagious vesicular rash (3). During primary infection, VZV establishes latency in sensory trigeminal and dorsal root ganglia. Reactivation from latency results in a secondary disease called herpes zoster (HZ), or shingles, that is more common in elderly people (4). HZ most frequently occurs in the thoracic or lumbar nerve segments and the distribution area of the trigeminal nerve, causing a painful rash in the corresponding dermatome. While the molecular mechanism for reactivation from latency is not well characterized, it is more frequent in immunocompromised patients (5). The most common sequela of HZ is postherpetic neuralgia (PHN). In addition, VZV reactivation can lead to zoster ophthalmicus, acute retinal necrosis, meningitis, and vasculopathy (6).The seroprevalence of VZV differs significantly between countries, but the majority of individuals are seropositive by the time of adolescence (7). While in otherwise healthy children and adolescents, primary VZV infection mostly resolves spontaneously without sequelae, severe symptoms may occur in immunocompromised people and during pregnancy (6). Vertical transmission of VZV during the first trimester causes congenital varicella syndrome (CVS), which is characterized by skin lesions, hypoplasia, low birth weight, and neurological dis...

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Section: Generation Of Monoclonal Antibodies Against Vzv Proteinssupporting

confidence: 86%

Comprehensive Analysis of Varicella-Zoster Virus Proteins Using a New Monoclonal Antibody Collection

Roviš

Bailer

Pothineni

et al. 2013

J Virol

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“…1), similarly to the transfer of Epstein–Barr virus to tonsil B cells 29 . VZV can also infect dendritic cells, which might facilitate spread to lymph nodes 30,31 . VZV-infected CD4 + T cells predominantly show a memory T cell phenotype and express activation markers and skin-homing proteins, such as cutaneous leukocyte antigen (CLA) and CC-chemokine receptor 4 (CCR4), and are thus more likely to circulate through skin and other tissues 28 .…”

Section: T Cell Tropismmentioning

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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“…During this time it has been proposed that VZV actively evades immune recognition in this period, since the development of adaptive immunity is delayed (reviewed in reference 1). We have postulated that VZV infection of dendritic cells (DCs) and/or modulation of the immune function of these potent antigen-presenting cells would provide a strategy that would enhance the capacity of the virus to be transported from the site of inoculation to the draining lymph nodes to infect T cells while also evading immune detection.We have previously shown that VZV can productively infect human DCs in vitro and in vivo (2,16,22). These studies included demonstration that productively infected immature monocytederived DCs (MDDCs) are unable to upregulate the functionally important immune molecules CD80, CD83, CD86, major histocompatibility complex I, and CCR7, which are required for DC maturation and induction of an effective antiviral immune response (2).…”

mentioning

confidence: 99%

“…We have previously shown that VZV can productively infect human DCs in vitro and in vivo (2,16,22). These studies included demonstration that productively infected immature monocytederived DCs (MDDCs) are unable to upregulate the functionally important immune molecules CD80, CD83, CD86, major histocompatibility complex I, and CCR7, which are required for DC maturation and induction of an effective antiviral immune response (2).…”

mentioning

confidence: 99%

Varicella-Zoster Virus Inhibition of the NF-κB Pathway during Infection of Human Dendritic Cells: Role for Open Reading Frame 61 as a Modulator of NF-κB Activity

Sloan

Henriquez

Kinchington

et al. 2012

J Virol

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V aricella-zoster virus (VZV) is an alphaherpesvirus causing chickenpox (varicella) during primary infection and shingles (herpes zoster) following reactivation from a latent infection. Following initial exposure to the virus, there is a 10-to 21-day incubation period before the appearance of the varicella rash. During this time it has been proposed that VZV actively evades immune recognition in this period, since the development of adaptive immunity is delayed (reviewed in reference 1). We have postulated that VZV infection of dendritic cells (DCs) and/or modulation of the immune function of these potent antigen-presenting cells would provide a strategy that would enhance the capacity of the virus to be transported from the site of inoculation to the draining lymph nodes to infect T cells while also evading immune detection.We have previously shown that VZV can productively infect human DCs in vitro and in vivo (2,16,22). These studies included demonstration that productively infected immature monocytederived DCs (MDDCs) are unable to upregulate the functionally important immune molecules CD80, CD83, CD86, major histocompatibility complex I, and CCR7, which are required for DC maturation and induction of an effective antiviral immune response (2). The expression of the immune molecules inhibited by VZV are largely regulated by the nuclear factor B (NF-B) signal transduction pathway (4,6,(12)(13)(14). The NF-B signal transduction pathway is an important regulator of innate immunity and inflammation that is triggered by a wide variety of stimuli, including virus infection, tumor necrosis factor alpha (TNF-␣), and other cytokines and pathogens (26,29). Activation of the NF-B pathway via pattern recognition receptors results in the phosphorylation of inhibitor of B kinase complex (IKK), which in turn phosphorylates IB, targeting it for ubiquitination and degradation, allowing NF-B proteins (p50 and p65) to translocate into the nucleus and bind to promoters containing NF-B response elements, initiating transcription of target genes (reviewed in references 26 and 29).Herpesviruses encode multiple proteins that function in immune evasion, and several herpesvirus proteins target and disrupt the NF-B pathway. Viral genes encoded by 27,28), cytomegalovirus (23,34), and herpes simplex virus 1 (HSV-1) (3, 9, 24) have been identified to regulate the NF-B pathway in a cell type-dependent manner. Jones and Arvin (17) reported that VZV inhibits the NF-B pathway in human fibroblasts in vitro and in vivo following the phosphorylation and ubiquitination of IB␣ but prior to the translocation of NF-B proteins into the nucleus.In the present study, we sought to extend these studies and examine the effect of VZV on the NF-B pathway within VZVinfected human MDDCs. Using flow cytometry, immunofluorescent staining, and Western blotting, we establish the point where VZV impacts the NF-B pathway in VZV antigen-positive DCs. In addition, using a transient-transfection approach and flow cytometry, we identified the E3 ubiquitin ligase domai...

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Impact of Varicella-Zoster Virus on Dendritic Cell Subsets in Human Skin during Natural Infection

Abstract: Varicella-zoster virus (VZV) causes varicella and herpes zoster

Cited by 62 publications

References 65 publications

Comprehensive Analysis of Varicella-Zoster Virus Proteins Using a New Monoclonal Antibody Collection

Comprehensive Analysis of Varicella-Zoster Virus Proteins Using a New Monoclonal Antibody Collection

Molecular mechanisms of varicella zoster virus pathogenesis

Varicella-Zoster Virus Inhibition of the NF-κB Pathway during Infection of Human Dendritic Cells: Role for Open Reading Frame 61 as a Modulator of NF-κB Activity

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