JC virus propagation is potentiated by glial replication and accelerated by demyelination-associated glial proliferation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA603990 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10990350.fastq.gz | Fastqsanger.gz | |||
| SRR10990351.fastq.gz | Fastqsanger.gz | |||
| SRR10990352.fastq.gz | Fastqsanger.gz | |||
| SRR10990353.fastq.gz | Fastqsanger.gz | |||
| SRR10990354.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.
2025-05-30 | GSE144538 | GEO
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 [scRNA-seq]
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Project description:Demyelination is a central pathological feature of multiple sclerosis and many other neurodegenerative diseases, and the cuprizone diet is a widely used model for studying this process. This study examines the transcriptional changes in key glial cell types—oligodendrocyte and astrocytes—during demyelination induced by a 4-week cuprizone diet. Bulk RNA sequencing was performed on these cells isolated using magnetic-activated cell sorting (MACS) from mice on either a normal diet or a 0.3% cuprizone diet. The experimental groups included: (1) oligodendrocytes and astrocytes from mice on a normal diet, and (2) oligodendrocytes and astrocytes from mice on a cuprizone diet. This study provides a comprehensive transcriptomic view of how these glial cell types respond to demyelination and will enhance our understanding of their individual and collective roles in this pathological process.
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Project description:Multiple Sclerosis (MS) is a neuroinflammatory disease characterized by demyelinated lesions in the CNS. Remyelination in MS is variable between individuals and tends to become less efficient with aging. Microglia and astrocytes are known to have critical roles in MS pathogenesis, but to what extent their activity is altered by remyelination failure remains unclear. To determine the effects of demyelination on neuroinflammation, we use two mouse models that genetically ablate myelinating oligodendrocytes. We use the Plp1-CreERT mouse line crossed with the Myrf fl/fl mouse line to induce genetic demyelination throughout the CNS following adult tamoxifen administration. Subsequent remyelination is mediated by the proliferation and differentiation of oligodendrocyte precursor cells (OPCs) to newly formed oligodendrocytes. To assess the consequences of remyelination failure, we deleted Myrf from both mature oligodendrocytes and OPCs using Myrf fl/fl; Sox10-CreERT mice, which both induces demyelination and impairs subsequent remyelination. To characterize the glial cells in these demyelinated mice, we performed single-nucleus RNA-sequencing (snRNAseq) of optic nerves at peak demyelination, generating an atlas of non-neuronal cells including oligodendrocyte lineage cells, astrocytes, microglia, endothelial cells, pericytes, arachnoid barrier cells, vascular and leptomeningeal cells.
2024-09-12 | GSE243788 | GEO
Project description:Strategies for treating progressive multiple sclerosis (MS) remain limited. Here, we found that miR-145-5p is overabundant uniquely in chronic lesion tissues from secondary progressive MS patients. We induced both acute and chronic demyelination in miR-145 knockout mice to determine its contributions to remyelination failure. Following acute demyelination, no advantage to miR-145 loss could be detected. However, after chronic demyelination, animals with miR-145 loss demonstrated increased remyelination and functional recovery, coincident with altered presence of astrocytes and microglia within the corpus callosum relative to wild-type animals. This improved response in miR-145 knockout animals coincided with a pathological upregulation of miR-145-5p in wild-type animals with chronic cuprizone exposure, paralleling human chronic lesions. Furthermore, miR-145 overexpression specifically in oligodendrocytes (OLs) severely stunted differentiation and negatively impacted survival. RNAseq analysis showed altered transcriptome in these cells with downregulated major pathways involved in myelination. Our data suggest that pathological accumulation of miR-145-5p is a distinctive feature of chronic demyelination and is strongly implicated in the failure of remyelination, possibly due to the inhibition of OL differentiation together with alterations in other glial cells. This is mirrored in chronic MS lesions, and thus miR-145-5p serves as a potential relevant therapeutic target in progressive forms of MS.
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Project description:Pathologies of the central nervous system (CNS) white matter often result in permanent functional deficits because mature mammalian projection neurons fail to regenerate long-distance axons after injury. A major barrier to axonal regenerative research is that the CNS axons that regenerate in response to experimental treatments stall growth before reaching their post-synaptic targets. Here, we test the hypothesis that interaction of regenerating axons with live oligodendrocytes, which were absent during developmental axon growth, stalls axonal growth. To test this hypothesis, first, we used single cell RNA-seq (scRNA-seq) and immunohistological analysis to investigate whether post-injury born oligodendrocytes incorporate into the glial scar after optic nerve injury. Then, we administered demyelination-inducing cuprizone (used in studies of multiple sclerosis), concurrently with the stimulation of axon regeneration by Pten knockdown (KD) in projection neurons after optic nerve injury. We found that post-injury born oligodendrocyte lineage cells incorporate into the glial scar, where they are susceptible to the demyelination diet treatment, which reduced their presence in the glial scar. We further found that the demyelination diet enhanced Pten KD-stimulated axon regeneration, and localized injection of cuprizone promoted axon regeneration. We also present a website for comparing the gene expression of scRNA-seq-profiled optic nerve oligodendrocyte lineage cells under physiological and pathophysiological conditions. Annotation of oligodendrocyte lineage cell subtypes, and normal or injured condition, are indicated in the last two rows of the cell matrix CSV file.
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