Kallikrein-mediated cytokeratin 10 degradation is required for VZV propagation in skin
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE136586 | GEO | 2019/08/29
REPOSITORIES: GEO
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Project description:Our aim was to investigate the interaction between epidermal differentiation and VZV infection. By means of a calcium-induced keratinocyte differentiation model and RNA-seq we show VZV infection has a profound effect on differentiating keratinocytes and hijacks the normal process of epidermal gene expression to generate a signature resembling patterns of gene expression seen in both heritable and acquired skin-blistering disorders. Analysis of the viral transcriptome provides evidence that VZV replication in skin is tightly linked to differentiation and critically, that late viral gene expression is associated with cellular differentiation. The experiment was performed on human primary keratinocytes under four conditions: undifferentiated/uninfected, uninfected/differentiated, VZV-infected/undifferentiated and VZV-infected/differentiated.
2014-05-29 | E-MTAB-1717 | biostudies-arrayexpress
Project description:During primary infection, varicella-zoster virus (VZV) is spread via lymphocytes to skin, where it induces a rash and establishes latency in sensory ganglia. A live, attenuated varicella vaccine (vOka) was generated by using the VZV Oka strain (pOka), but the molecular basis for vOka attenuation remains unknown. Little is known concerning the effects of wild-type or attenuated VZV on cellular gene regulation in the host cells that are critical for pathogenesis. In this study, transcriptional profiles of primary human T cells and fibroblasts infected with VZV in cell culture were determined by using 40,000-spot human cDNA microarrays. Cellular gene transcription in human skin xenografts in SCID mice that were infected with VZV in vivo was also evaluated. The profiles of cellular gene transcripts that were induced or inhibited in infected human foreskin fibroblasts (HFFs), T cells, and skin in response to pOka and vOka infection were similar. However, significant alterations in cellular gene regulation were observed among the three differentiated human cell types that were examined, suggesting specific differences in the biological consequences of VZV infection related to the target cell. Changes in cellular gene transcription detected by microarray analysis were confirmed for selected genes by quantitative real-time reverse transcription-PCR analysis of VZV-infected cells. Interestingly, the transcription of caspase 8 was found to be decreased in infected T cells but not in HFFs or skin, which may signify a tissue-specific antiapoptosis mechanism. The use of microarrays to demonstrate differences in effects on host cell genes in primary, biologically relevant cell types provides background information for experiments to link these various response phenotypes with mechanisms of VZV pathogenesis that are important for the natural course of human infection.
2005-10-07 | E-SMDB-1945 | biostudies-arrayexpress
Project description:During primary infection, varicella-zoster virus (VZV) is spread via lymphocytes to skin, where it induces a rash and establishes latency in sensory ganglia. A live, attenuated varicella vaccine (vOka) was generated by using the VZV Oka strain (pOka), but the molecular basis for vOka attenuation remains unknown. Little is known concerning the effects of wild-type or attenuated VZV on cellular gene regulation in the host cells that are critical for pathogenesis. In this study, transcriptional profiles of primary human T cells and fibroblasts infected with VZV in cell culture were determined by using 40,000-spot human cDNA microarrays. Cellular gene transcription in human skin xenografts in SCID mice that were infected with VZV in vivo was also evaluated. The profiles of cellular gene transcripts that were induced or inhibited in infected human foreskin fibroblasts (HFFs), T cells, and skin in response to pOka and vOka infection were similar. However, significant alterations in cellular gene regulation were observed among the three differentiated human cell types that were examined, suggesting specific differences in the biological consequences of VZV infection related to the target cell. Changes in cellular gene transcription detected by microarray analysis were confirmed for selected genes by quantitative real-time reverse transcription-PCR analysis of VZV-infected cells. Interestingly, the transcription of caspase 8 was found to be decreased in infected T cells but not in HFFs or skin, which may signify a tissue-specific antiapoptosis mechanism. The use of microarrays to demonstrate differences in effects on host cell genes in primary, biologically relevant cell types provides background information for experiments to link these various response phenotypes with mechanisms of VZV pathogenesis that are important for the natural course of human infection. A pathogenicity experiment design type is where an infective agent such as a bacterium, virus, protozoan, fungus etc. infects a host organism(s) and the infective agent is assayed. Computed
2005-11-23 | E-GEOD-3666 | biostudies-arrayexpress
Project description:During primary infection, varicella-zoster virus (VZV) is spread via lymphocytes to skin, where it induces a rash and establishes latency in sensory ganglia. A live, attenuated varicella vaccine (vOka) was generated by using the VZV Oka strain (pOka), but the molecular basis for vOka attenuation remains unknown. Little is known concerning the effects of wild-type or attenuated VZV on cellular gene regulation in the host cells that are critical for pathogenesis. In this study, transcriptional profiles of primary human T cells and fibroblasts infected with VZV in cell culture were determined by using 40,000-spot human cDNA microarrays. Cellular gene transcription in human skin xenografts in SCID mice that were infected with VZV in vivo was also evaluated. The profiles of cellular gene transcripts that were induced or inhibited in infected human foreskin fibroblasts (HFFs), T cells, and skin in response to pOka and vOka infection were similar. However, significant alterations in cellular gene regulation were observed among the three differentiated human cell types that were examined, suggesting specific differences in the biological consequences of VZV infection related to the target cell. Changes in cellular gene transcription detected by microarray analysis were confirmed for selected genes by quantitative real-time reverse transcription-PCR analysis of VZV-infected cells. Interestingly, the transcription of caspase 8 was found to be decreased in infected T cells but not in HFFs or skin, which may signify a tissue-specific antiapoptosis mechanism. The use of microarrays to demonstrate differences in effects on host cell genes in primary, biologically relevant cell types provides background information for experiments to link these various response phenotypes with mechanisms of VZV pathogenesis that are important for the natural course of human infection. A pathogenicity experiment design type is where an infective agent such as a bacterium, virus, protozoan, fungus etc. infects a host organism(s) and the infective agent is assayed. Keywords: pathogenicity_design
2005-11-24 | GSE3666 | GEO
Project description:With Varicella-Zoster Virus (VZV) being an exclusive human pathogen, human induced pluripotent stem cell (hiPSC)-derived neural cell culture models are an emerging tool to investigate VZV neuro-immune interactions. Using a compartmentalized hiPSC-derived neuronal model allowing axonal VZV infection, we previously demonstrated that paracrine interferon (IFN)-α2 signalling is required to activate a broad spectrum of interferon-stimulated genes able to counteract a productive VZV infection in hiPSC-neurons. In this new study, we now investigated whether innate immune signalling by VZV-challenged macrophages was able to orchestrate an antiviral immune response in VZV-infected hiPSC-neurons. In order to establish an isogenic hiPSC-neuron / hiPSC-macrophage co-culture model, hiPSC-macrophages were generated and characterised for phenotype, gene expression, cytokine production and phagocytic capacity. Even though immunological competence of hiPSC-macrophages was shown following stimulation with the VZV mimic poly(dA:dT) or treatment with IFN-α2, hiPSC-macrophages in co-culture with VZV-infected hiPSC-neurons were unable to mount an antiviral immune response capable of suppressing a productive neuronal VZV infection. Subsequently, a comprehensive RNA-Seq analysis confirmed the lack of strong immune responsiveness by hiPSC-neurons and hiPSC-macrophages upon, respectively, VZV infection or challenge. This may suggest the need of other cell types, like T-cells or other innate immune cells, to (co-)orchestrate an efficient antiviral immune response against VZV-infected neurons.
2023-04-19 | GSE228390 | GEO
Project description:The highly conserved herpesvirus glycoprotein complex, gB/gH-gL, mediates membrane fusion during virion entry and cell-cell fusion. Varicella-zoster virus (VZV) characteristically forms multi-nucleated cells, or syncytia, during the infection of human tissues but little is known about this process. The cytoplasmic domain of VZV gB (gBcyt) has been implicated in cell-cell fusion regulation because a gB[Y881F] substitution causes hyperfusion. The gBcyt regulation is necessary for VZV pathogenesis as the hyperfusogenic mutant gB[Y881F] is severely attenuated in human skin xenografts. In this study, gBcyt regulated fusion was investigated by comparing melanoma cells infected with wild type-like VZV or hyperfusogenic mutants. The gB[Y881F] mutant exhibited dramatically accelerated syncytia formation in melanoma cells caused by fusion of infected cells with many uninfected cells, increased cytoskeleton reorganization and rapid displacement of nuclei to dense central structures when compared to pOka using live cell confocal microscopy. VZV and human transcriptomes were concurrently investigated using RNA-seq to identify viral and cellular responses induced when the gBcyt regulation was disrupted by the gB[Y881F] substitution. The expression of four vital VZV genes, ORF61 and glycoproteins, gC, gE and gI, was significantly reduced at 36 hours post infection for the hyperfusogenic mutants. Importantly, hierarchical clustering demonstrated an association of differential gene expression with dysregulated gBcyt-mediated fusion. A subset of Ras GTPase genes linked to membrane remodeling were upregulated in cells infected with the hyperfusogenic mutants. These data implicate the gBcyt in the regulation gB fusion function that, if unmodulated, triggers cellular processes leading to hyperfusion that attenuates VZV infection.
2017-03-01 | GSE85493 | GEO
Project description:Neuronal reactivation of latent varicella zoster virus (VZV) causes debilitating and protracted pain (post herpetic neuralgia: PHN) in a significant fraction of patients. Productive infection of VZV seems to occur only in humans and primates, so VZV-infected human cells (e.g., MEWO cell line) are used to transmit VZV to rodents. A commonly accepted method of assessing nociception is ipsilateral nocifensive (pain avoidance) behavior in rats which have been injected in a footpad. No such behavioral change is associated with the contralateral (uninjected) footpad. Uninfected MEWO cells or VZV-infected MEWO cells were inoculated into the glabrous region of the right rear footpad of male Sprague-Dawley rats. By 9 days post-inoculation, there was a VZV-dependent decrease in the frequency of neurites that extend from the dermis past the stratum basale layer of the footpad epidermis. Between 7 days and 21 days post-inoculation there was a VZV-dependent increase in nocifensive behaviours in the rats. All VZV-dependent effects occurred in the absence of the productive VZV infection. That is, the virus entered rodent cells and expressed immediate early and early genes, but did not express late genes, synthesize viral DNA, or release infectious virions. Animals which had developed VZV-dependent nocifensive behaviours at 10 days were euthanized, and dorsal root ganglia (L4,5) ipsilateral to inoculation were taken for microarray analysis. Dorsal root ganglia from matching control animals were also analyzed. Control (uninfected MEWO cells) or VZV-infected MEWO cells were inoculated into the glabrous region of the right rear footpad of male Sprague-Dawley rats. After development of ipsilateral nocifensive behaviour in the VZV-infected animals, the ipsilateral dorsal root ganglia (L4,5) from infected and control animals were taken for microarray analysis.
2015-03-31 | E-GEOD-64345 | biostudies-arrayexpress
Project description:The cellular transcriptomes of VZV-infected fibroblasts and T-lymphocytes have been reported, but not that of human neurons. In order to determine the transcriptional response of human neurons to VZV infection, we generated 95%-pure populations of neurons from hESC, infected them with recombinant GFP-expressing cell-free VZV, and compared their transcriptome to that of human foreskin fibroblasts infected in parallel, using Agilent microarrays. Applying a twofold-change as the cutoff (p-value<0.05), we observed that transcription of 1654 fibroblast and 340 neuronal genes were upregulated, and 955 fibroblast and 38 neuronal genes were downregulated by VZV infection. 223 of these infection-regulated genes were unique to neurons. Gene ontology enrichment analysis revealed several clusters of genes regulated by VZV in neurons and fibroblasts differed. For example, neurons did not show upregulation of innate immune responses, NF-kappaB, response to stress and DNA repair clusters, in contrast to fibroblasts that upregulated these groups. This is the first study of the response of genetically normal human neurons to viral infection. Two-condition experiment, VZV-GFP23- fibroblast cells vs. fibroblast cells, and VZV-GFP23- neuron cells vs. neuron cells. Data from two biological replicates and two technical replicates were used for each condition.
2014-04-22 | E-GEOD-54385 | biostudies-arrayexpress
Project description:Neuronal reactivation of latent varicella zoster virus (VZV) causes debilitating and protracted pain (post herpetic neuralgia: PHN) in a significant fraction of patients. Productive infection of VZV seems to occur only in humans and primates, so VZV-infected human cells (e.g., MEWO cell line) are used to transmit VZV to rodents. A commonly accepted method of assessing nociception is ipsilateral nocifensive (pain avoidance) behavior in rats which have been injected in a footpad. No such behavioral change is associated with the contralateral (uninjected) footpad. Uninfected MEWO cells or VZV-infected MEWO cells were inoculated into the glabrous region of the right rear footpad of male Sprague-Dawley rats. By 9 days post-inoculation, there was a VZV-dependent decrease in the frequency of neurites that extend from the dermis past the stratum basale layer of the footpad epidermis. Between 7 days and 21 days post-inoculation there was a VZV-dependent increase in nocifensive behaviours in the rats. All VZV-dependent effects occurred in the absence of the productive VZV infection. That is, the virus entered rodent cells and expressed immediate early and early genes, but did not express late genes, synthesize viral DNA, or release infectious virions. Animals which had developed VZV-dependent nocifensive behaviours at 10 days were euthanized, and dorsal root ganglia (L4,5) ipsilateral to inoculation were taken for microarray analysis. Dorsal root ganglia from matching control animals were also analyzed.
2015-03-31 | GSE64345 | GEO