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 5

Astrocytes and GPCs are sufficient to support viral replication and spread in vivo.

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Astrocytes and GPCs are sufficient to support viral replication and spre...
(A) JCV introduced into myelin WT Rag1–/– mice (colonized with human GPCs and astrocytes, but not oligodendrocytes) yielded viral propagation and geographic spread as rapid and extensive as that in human glial chimeric Rag2–/– Mbpshi/shi mice (in which human oligodendroglia were densely represented). Shown are distributions of T-Ag+ and VP1+ cells mapped in 14-μm sagittal sections of 3 different Rag1–/– mice injected with JCV as adults, 12 weeks previously. Infected human cells were widely distributed, despite the absence of human oligodendroglia. (B) Sagittal section along the callosal length of a chimeric myelin WT Rag1–/– mouse 12 weeks after infection, showing widespread infection and VP1 expression by GFAP+ subcortical human astrocytes and GFAP– cortical human astrocytes and GPCs. (D and E) Higher-magnification views showing the predominance of infected cells (arrowheads) in Rag1–/– cortical grey, including both T-Ag+ (D) and VP1+ (E) glia, manifesting the typical hypertrophic nuclei of cells that have undergone viral replication. (F) Conversely, VP1+ glia in the corpus callosum of a human glial chimeric Rag2–/– Mbpshi/shi mouse 12 weeks after type 1A (Mad-1) JCV infection showed the predominant white matter spread of virus in these mice, which manifested both oligodendrocytic and astrocytic infection (compare with the Rag1–/– section in C). Notably, since JCV can only infect human cells, the potential volume of infection in these mice was limited by the geographic dispersal of the resident human oligodendrocyte progenitor cells. Since these mice were given only forebrain injections so as to produce forebrain-only human glial chimeras, all JCV infection in these mice was limited to the forebrain. Cx, cerebral cortex; CC, corpus callosum. Scale bars: 100 μm (B, C, and F); 50 μm (D and E).