Human glial chimeric mice reveal astrocytic dependence of JC virus infection
Yoichi Kondo, … , Leonid Gorelik, Steven A. Goldman
Yoichi Kondo, … , Leonid Gorelik, Steven A. Goldman
Published November 17, 2014
Citation Information: J Clin Invest. 2014;124(12):5323-5336. https://doi.org/10.1172/JCI76629.
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Human glial chimeric mice reveal astrocytic dependence of JC virus infection

Abstract

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.

Authors

Yoichi Kondo, Martha S. Windrem, Lisa Zou, Devin Chandler-Militello, Steven J. Schanz, Romane M. Auvergne, Sarah J. Betstadt, Amy R. Harrington, Mahlon Johnson, Alexander Kazarov, Leonid Gorelik, Steven A. Goldman

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Figure 2

JCV replicates more rapidly and efficiently in astroglia than in oligodendrocytes in vivo.

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JCV replicates more rapidly and efficiently in astroglia than in oligode...
JCV induced the expression of the major early and late viral gene products (T-Ag and VP1 protein, respectively) throughout the corpus callosum of human glial chimeric Rag2–/– Mbpshi/shi mice. (A) Confocal images of infected oligodendrocytes, astrocytes, and GPCs in Rag2–/– Mbpshi/shi mice neonatally engrafted with human GPCs and infected with type 1A (Mad-1) JCV for 12 weeks. (B) By 12 weeks, infected astrocytes were highly abundant and largely magnocellular, with overtly enlarged nuclei and bizarrely fibrotic processes. (C) In contrast, substantial human oligodendrocytic loss was evident by 12 weeks after infection, and most of the infected remainder expressed T-Ag (arrowheads), as exemplified by the T-Ag+MBP+ oligodendroglia shown; only human oligodendroglia expressed MBP in Rag2–/– Mbpshi/shi brain. (D) Infection was restricted to human cells; in this example, unengrafted mouse corpus callosum manifested no evidence of infection 12 weeks after JCV injection. Scale bars: 20 μm (A); 50 μm (B and C); 100 μm (D).