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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Research Article

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 4

Viral propagation exhibits cell type–selective spread.

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Viral propagation exhibits cell type–selective spread. JCV spread in viv...
JCV spread in vivo was tracked by immunostaining human glial chimeric Rag2–/– Mbpshi/shi brains for both T-Ag and VP1, each as a function of time after infection. In these chimeric Rag2–/– Mbpshi/shi mice, a large proportion of oligodendrocytes, as well as GPCs and astrocytes, were human. (A) Sagittal sections of 3 different infected chimeras at each of 3 time points; individual VP1+ cells are dot-mapped. VP1+ human cells became progressively more widespread with time, with JCV infection progressing from the site of viral injection to include much of the forebrain white matter by 12 weeks postinfection, with marked cortical spread by that point as well. (B) T-Ag+ and VP1+ cells, representing all JCV-infected cells and those in which viral replication has occurred, respectively, both accumulated as a function of time. (C) The number of T-Ag+ astrocytes (GFAP+) and GPCs (NG2+) was significantly higher than that of T-Ag+ oligodendroglia (MBP+) at all time points examined (P < 0.01, repeated-measures 1-way ANOVA). Furthermore, the in vivo rates of accumulation of T-Ag+ astrocytes and GPCs (reflecting the rate of infection among each cell type, estimated by regression line slope) were each significantly higher than that of oligodendrocytes (P < 0.01, linear regression). (D–F) Despite their marked differences in T-Ag–defined infectivity and spread, astrocytes and oligodendrocytes did not differ in their rates of accumulation of VP1+ infectants, likely reflecting the rapid lytic loss of cells at that stage. *P < 0.05; **P < 0.01; ***P < 0.001.