JC virus propagation is potentiated by glial replication and accelerated by demyelination-associated glial proliferation [scRNA-seq]
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ABSTRACT:
PROVIDER: PRJNA604228 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10995703.fastq.gz | Fastqsanger.gz | |||
| SRR10995704.fastq.gz | Fastqsanger.gz |
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Project description:Progressive multifocal leukoencephalopathy (PML) is a demyelinating infection of the brain of immunosuppressed individuals, mediated by the gliotropic polyomavirus JCV. JCV replicates in mitotically-competent human glial progenitor cells and astrocytes, which are triggered to divide in the setting of viral T antigen-mediated cell cycle entry, allowing viral replication; the death of mitotically-incompetent oligodendrocytes occurs secondarily, largely through T antigen-mediated apoptosis. This observation suggested that JCV infection might be potentiated by astrocytic replication, and hence accelerated in the setting of mitotic gliogenesis. To test this hypothesis, we tagged dividing human glia in vitro with bromodeoxyuridine (BrdU), then infected them with JCV MAD1, and confirmed that proliferating human astrocytes are more supportive of JCV propagation than mitotically quiescent cells. In vitro, scratch assays confirmed that viral propagation was greatly enhanced in peri-scratch regions of dividing glia. JCV infection of human glial chimeras established that infection was greatly accentuated by cuprizone-mediated demyelination, which was associated with increased glial progenitor cell proliferation. JCV infection in vivo was associated with caspase3-defined death of uninfected as well as infected oligodendrocytes, suggesting the contribution of bystander death to JCV-associated demyelination. These results suggest that JCV propagation in PML may be potentiated by glial cell division, and that the accentuated glial cell division and hence DNA replication attending acute demyelination might provide an especially favorable environment for JCV propagation and PML progression. These data thus argue for the aggressive prevention of new demyelinating events in patients at risk for PML.
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Project description:JC virus propagation is potentiated by glial replication and accelerated by demyelination-associated glial proliferation
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Project description:Progressive multifocal leukoencephalopathy (PML) is a demyelinating infection of the brain of immunosuppressed individuals, mediated by the gliotropic polyomavirus JCV. JCV replicates in mitotically-competent human glial progenitor cells and astrocytes, which are triggered to divide in the setting of viral T antigen-mediated cell cycle entry, allowing viral replication; the death of mitotically-incompetent oligodendrocytes occurs secondarily, largely through T antigen-mediated apoptosis. This observation suggested that JCV infection might be potentiated by astrocytic replication, and hence accelerated in the setting of mitotic gliogenesis. To test this hypothesis, we tagged dividing human glia in vitro with bromodeoxyuridine (BrdU), then infected them with JCV MAD1, and confirmed that proliferating human astrocytes are more supportive of JCV propagation than mitotically quiescent cells. In vitro, scratch assays confirmed that viral propagation was greatly enhanced in peri-scratch regions of dividing glia. JCV infection of human glial chimeras established that infection was greatly accentuated by cuprizone-mediated demyelination, which was associated with increased glial progenitor cell proliferation. JCV infection in vivo was associated with caspase3-defined death of uninfected as well as infected oligodendrocytes, suggesting the contribution of bystander death to JCV-associated demyelination. These results suggest that JCV propagation in PML may be potentiated by glial cell division, and that the accentuated glial cell division and hence DNA replication attending acute demyelination might provide an especially favorable environment for JCV propagation and PML progression. These data thus argue for the aggressive prevention of new demyelinating events in patients at risk for PML.
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Project description:Candidatus Electronema sp. JC strain:JC Genome sequencing
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Project description:JC virus (JCV) is a ubiquitous human polyomavirus that causes the demyelinating disease Progressive Multifocal Leukoencephalopathy (PML). JCV replicates in limited cell types in culture, predominantly in human glial cells. Thus, productive JCV infection is an indicator of the host cell transcription environment. Following introduction of a replication defective SV40 mutant that expressed large T protein into a heterogeneous culture of human fetal brain cells, multiple phenotypes became immortalized (SVG cells). A subset of SVG cells could support JCV replication. This mixed culture was called SVG cells. In the current study, clonal cell lines were selected from the original SVG cell culture. The SVG-5F4 clone showed low levels of viral growth. The SVG-10B1 clone was highly permissive for JCV DNA replication and gene expression. Microarray analysis revealed that viral infection did not significantly change gene expression in these cells. More resistant 5F4 cells expressed high levels of transcription factors known to inhibit JCV transcription. Interestingly, 5F4 cells highly expressed RNA of markers of Bergman or radial glia and 10B1 cells had high expression of markers of immature glial cells and activation of transcription regulators important for stem/progenitor cell self-renewal. These SVG-derived clonal cell lines provide a biologically relevant model to investigate cell type differences in JCV host range and pathogenesis, as well as neural development. 13 Human samples: 3 SVG 10B1 clones 14 days post mock-infection, 3 SVG 10B1 clones 14 days post JCV Mad-4 strain infection, 3 SVG 5F4 clones 14 days post mock-infection, 4 SVG 5F4 clones 14 days post JCV Mad-4 strain infection.
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Project description:JC virus (JCV) is a ubiquitous human polyomavirus that causes the demyelinating disease Progressive Multifocal Leukoencephalopathy (PML). JCV replicates in limited cell types in culture, predominantly in human glial cells. Thus, productive JCV infection is an indicator of the host cell transcription environment. Following introduction of a replication defective SV40 mutant that expressed large T protein into a heterogeneous culture of human fetal brain cells, multiple phenotypes became immortalized (SVG cells). A subset of SVG cells could support JCV replication. This mixed culture was called SVG cells. In the current study, clonal cell lines were selected from the original SVG cell culture. The SVG-5F4 clone showed low levels of viral growth. The SVG-10B1 clone was highly permissive for JCV DNA replication and gene expression. Microarray analysis revealed that viral infection did not significantly change gene expression in these cells. More resistant 5F4 cells expressed high levels of transcription factors known to inhibit JCV transcription. Interestingly, 5F4 cells highly expressed RNA of markers of Bergman or radial glia and 10B1 cells had high expression of markers of immature glial cells and activation of transcription regulators important for stem/progenitor cell self-renewal. These SVG-derived clonal cell lines provide a biologically relevant model to investigate cell type differences in JCV host range and pathogenesis, as well as neural development.
2013-10-17 | GSE45639 | GEO
Project description:Human and animal viruses possess remarkable capabilities in hijacking host processes to facilitate viral infection. Viruses use various strategies to target antiviral response mechanisms while promoting cellular phenotypic states that benefit viral replication. Viruses that replicate and assemble in the nucleus, including human pathogenic DNA viruses, need to balance maximal use of the host DNA replication machinery while at the same time avoid damage to the nucleus before generating a large number of viruses that will support the spread of infection. We have identified a novel mechanism of virus interference with the cell nucleus that involves virus-mediated modulation of nuclear mechanical properties. One of the most widespread human viruses, the JC polyomavirus, interferes with nuclear architecture to form virus-occupied space and substantially reduces the rigidity of the infected human cell nucleus. The JC virus's impact on nuclear rigidity is mediated by the viral nonstructural protein, Agnoprotein (Agno). The Agno interference with nuclear mechanics is governed by structurally diverse mimics of host proteins that support chromatin interaction with the key chromatin regulator, heterochromatin protein 1 alpha (HP1α), and is critical for JC virus infection in vitro. The ability to control chromatin organization and thus nuclear mechanics reveals a previously unknown virus strategy of hijacking the mechanism controlling nuclear physical properties to maximize virus production within the nucleus.
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