Human glial chimeric mice reveal astrocytic dependence of JC virus infection
| Autor: | Romane Auvergne, Steven J. Schanz, Mahlon D. Johnson, Martha S. Windrem, Alexander Kazarov, Devin Chandler-Militello, Leonid Gorelik, Steven A. Goldman, Lisa Zou, Yoichi Kondo, Amy Harrington, Sarah J. Betstadt |
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| Rok vydání: | 2014 |
| Předmět: |
Male
viruses JC virus Apoptosis Biology medicine.disease_cause Virus Replication Virus 03 medical and health sciences Mice 0302 clinical medicine Antigen medicine Demyelinating disease Animals Humans Progenitor cell Antigens Viral Tumor 030304 developmental biology 0303 health sciences Transplantation Chimera Progressive multifocal leukoencephalopathy Stem Cells JC Virus Infection Leukoencephalopathy Progressive Multifocal virus diseases General Medicine medicine.disease Virology JC Virus 3. Good health Disease Models Animal Viral replication nervous system Astrocytes Immunology Commentary Heterografts Capsid Proteins Female 030217 neurology & neurosurgery Stem Cell Transplantation |
| Zdroj: | The Journal of clinical investigation. 124(12) |
| ISSN: | 1558-8238 |
| Popis: | Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease triggered by infection with the human gliotropic JC virus (JCV). Due to the human-selective nature of the virus, there are no animal models available to investigate JCV pathogenesis. To address this issue, we developed mice with humanized white matter by engrafting human glial progenitor cells (GPCs) into neonatal immunodeficient and myelin-deficient mice. Intracerebral delivery of JCV resulted in infection and subsequent demyelination of these chimeric mice. Human GPCs and astrocytes were infected more readily than oligodendrocytes, and viral replication was noted primarily in human astrocytes and GPCs rather than oligodendrocytes, which instead expressed early viral T antigens and exhibited apoptotic death. Engraftment of human GPCs in normally myelinated and immunodeficient mice resulted in humanized white matter that was chimeric for human astrocytes and GPCs. JCV effectively propagated in these mice, which indicates that astroglial infection is sufficient for JCV spread. Sequencing revealed progressive mutation of the JCV capsid protein VP1 after infection, suggesting that PML may evolve with active infection. These results indicate that the principal CNS targets for JCV infection are astrocytes and GPCs and that infection is associated with progressive mutation, while demyelination is a secondary occurrence, following T antigen-triggered oligodendroglial apoptosis. More broadly, this study provides a model by which to further assess the biology and treatment of human-specific gliotropic viruses. |
| Databáze: | OpenAIRE |
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