Molecular mechanisms of varicella zoster virus pathogenesis

Zerboni, Leigh; Sen, Nandini; Oliver, Stefan L.; Arvin, Ann M.

doi:10.1038/nrmicro3215

Cited by 358 publications

(351 citation statements)

References 107 publications

(181 reference statements)

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“…The VZV O-Glycoproteome-We identified 53 O-glycosylation sites on six of nine VZV envelope glycoproteins (Table 1 and supplemental Data Sets S1-S3), combining results obtained from infected cell lysate and clinical VZV sample (39,40). Four envelope glycoproteins are essential for VZV replication in vitro: gB, gH, gL, and gE, of which gB and the gH-gL complex is thought to mediate both virion-cell and cell-cell fusion (41)(42)(43)(44).…”

Section: Mapping O-glycosites In Human Herpesvirusesmentioning

confidence: 99%

Global Mapping of O-Glycosylation of Varicella Zoster Virus, Human Cytomegalovirus, and Epstein-Barr Virus

Bagdonaite

Nordén

Joshi

et al. 2016

Journal of Biological Chemistry

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Herpesviruses are among the most complex and widespread viruses, infection and propagation of which depend on envelope proteins. These proteins serve as mediators of cell entry as well as modulators of the immune response and are attractive vaccine targets. Although envelope proteins are known to carry glycans, little is known about the distribution, nature, and functions of these modifications. This is particularly true for O-glycans; thus we have recently developed a "bottom up" mass spectrometry-based technique for mapping O-glycosylation sites on herpes simplex virus type 1. We found wide distribution of O-glycans on herpes simplex virus type 1 glycoproteins and demonstrated that elongated O-glycans were essential for the propagation of the virus. Here, we applied our proteome-wide discovery platform for mapping O-glycosites on representative and clinically significant members of the herpesvirus family: varicella zoster virus, human cytomegalovirus, and Epstein-Barr virus. We identified a large number of O-glycosites distributed on most envelope proteins in all viruses and further demonstrated conserved patterns of O-glycans on distinct homologous proteins. Because glycosylation is highly dependent on the host cell, we tested varicella zoster virus-infected cell lysates and clinically isolated virus and found evidence of consistent O-glycosites. These results present a comprehensive view of herpesvirus O-glycosylation and point to the widespread occurrence of O-glycans in regions of envelope proteins important for virus entry, formation, and recognition by the host immune system. This knowledge enables dissection of specific functional roles of individual glycosites and, moreover, provides a framework for design of glycoprotein vaccines with representative glycosylation.

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Section: Mapping O-glycosites In Human Herpesvirusesmentioning

confidence: 99%

Global Mapping of O-Glycosylation of Varicella Zoster Virus, Human Cytomegalovirus, and Epstein-Barr Virus

Bagdonaite

Nordén

Joshi

et al. 2016

Journal of Biological Chemistry

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“…severe combined immunodeficiency (SCID) mouse (14). In turn, replicate xenografts are inoculated with VZV-infected cells and then harvested at 7, 14, and 21 d after infection.…”

Section: Autophagy In Vzv-infected Human Skin Xenografts In the Scidmentioning

confidence: 99%

Autophagic flux without a block differentiates varicella-zoster virus infection from herpes simplex virus infection

Buckingham

Carpenter

Jackson

et al. 2014

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

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Autophagy is a process by which misfolded and damaged proteins are sequestered into autophagosomes, before degradation in and recycling from lysosomes. We have extensively studied the role of autophagy in varicella-zoster virus (VZV) infection, and have observed that vesicular cells are filled with >100 autophagosomes that are easily detectable after immunolabeling for the LC3 protein. To confirm our hypothesis that increased autophagosome formation was not secondary to a block, we examined all conditions of VZV infection as well as carrying out two assessments of autophagic flux. We first investigated autophagy in human skin xenografts in the severe combined immunodeficiency (SCID) mouse model of VZV pathogenesis, and observed that autophagosomes were abundant in infected human skin tissues. We next investigated autophagy following infection with sonically prepared cell-free virus in cultured cells. Under these conditions, autophagy was detected in a majority of infected cells, but was much less than that seen after an infected-cell inoculum. In other words, inoculation with lower-titered cell-free virus did not reflect the level of stress to the VZV-infected cell that was seen after inoculation of human skin in the SCID mouse model or monolayers with higher-titered infected cells. Finally, we investigated VZVinduced autophagic flux by two different methods (radiolabeling proteins and a dual-colored LC3 plasmid); both showed no evidence of a block in autophagy. Overall, therefore, autophagy within a VZV-infected cell was remarkably different from autophagy within an HSV-infected cell, whose genome contains two modifiers of autophagy, ICP34.5 and US11, not present in VZV.V ZV induces macroautophagy (hereafter referred to as autophagy) in skin cells within the typical exanthem associated with either primary VZV infection (varicella or chickenpox) or VZV reactivation (herpes zoster or shingles). During prior studies, the extent of autophagy was gauged by enumeration of autophagosomes by both 2D and 3D microscopy (1, 2). The usual number of autophagosomes seen by 3D animation was 100 per infected cell, but sometimes approached 200 per cell. In contrast, a typical nonstressed cell usually has fewer than 4 autophagosomes (3, 4). When monolayers were inoculated with VZV-infected cells, the traditional method for VZV infection, autophagy was again easily seen after enumeration of autophagosomes and immunoblotting for the LC3-phosphatidylethanolamine conjugate (LC3-II). Again these results suggested that autophagic flux was present during VZV infection in cultured cells.As part of a more extensive assessment of autophagy after VZV-induced cellular stress, we have now investigated autophagy in infected human skin xenografts from the SCID mouse model of VZV infection. This model is the most accurate representation of the skin manifestation of varicella in the human host (5, 6). Finally, we addressed an important point about the nature of VZV-induced autophagy. Because the number of autophagosomes seen in the human vesicle...

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“…In the course of infection, VZV induces pathological abnormalities mainly in skin and nerves. To date, VZV protein function in cells and tissues has been studied extensively by mutagenesis of the VZV genome together with the use of human fetal tissues either cultured ex vivo or engrafted in severe combined immunodeficient (SCID) mice in vivo, and many viral proteins have been identified to be implicated in VZV skin-and/or neuro-tropism (Zhang et al, 2010;Zerboni et al, 2014;Wang et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Varicella-zoster virus ORF7 interacts with ORF53 and plays a role in its trans-Golgi network localization

Wang

Pan

et al. 2017

Virol. Sin.

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Varicella-zoster virus (VZV) is a neurotropic alphaherpesvirus that causes chickenpox andshingles. ORF7 is an important virulence determinant of VZV in both human skin and nerve tissues, however, its specific function and involved molecular mechanism in VZV pathogenesis remain largely elusive. Previous yeast two-hybrid studies on intraviral protein-protein interaction network in herpesviruses have revealed that VZV ORF7 may interact with ORF53, which is a virtually unstudied but essential viral protein. The aim of this study is to identify and characterize VZV ORF53, and to investigate its relationship with ORF7. For this purpose, we prepared monoclonal antibodies against ORF53 and, for the first time, characterized it as a ~40 kDa viral protein predominantly localizing to the trans-Golgi network of the infected host cell. Next, we further confirmed the interaction between ORF7 and ORF53 by co-immunoprecipitation and co-localization studies in both plasmid-transfected and VZV-infected cells. Moreover, interestingly, we found that ORF53 lost its trans-Golgi network localization and became dispersed in the cytoplasm of host cells infected with an ORF7-deleted recombinant VZV, and thus ORF7 seems to play a role in normal subcellular localization of ORF53. Collectively, these results suggested that ORF7 and ORF53 may function as a complex during infection, which may be implicated in VZV pathogenesis. KEYWORDSvaricella-zoster virus (VZV); ORF7; ORF53; protein-protein interaction; trans-Golgi network

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Molecular mechanisms of varicella zoster virus pathogenesis

Cited by 358 publications

References 107 publications

Global Mapping of O-Glycosylation of Varicella Zoster Virus, Human Cytomegalovirus, and Epstein-Barr Virus

Global Mapping of O-Glycosylation of Varicella Zoster Virus, Human Cytomegalovirus, and Epstein-Barr Virus

Autophagic flux without a block differentiates varicella-zoster virus infection from herpes simplex virus infection

Varicella-zoster virus ORF7 interacts with ORF53 and plays a role in its trans-Golgi network localization

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