Human glial chimeric mice reveal astrocytic dependence of JC virus infection.
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.
Yoichi
Y
Kondo
Martha S
MS
Windrem
Lisa
L
Zou
Devin
D
Chandler-Militello
Steven J
SJ
Schanz
Romane M
RM
Auvergne
Sarah J
SJ
Betstadt
Amy R
AR
Harrington
Mahlon
M
Johnson
Alexander
A
Kazarov
Leonid
L
Gorelik
Steven A
SA
Goldman
D000818:Animals; D000957:Antigens, Viral, Tumor / Q000235:genetics / Q000276:immunology; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001253:Astrocytes / Q000276:immunology* / Q000473:pathology; D036022:Capsid Proteins / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D064593:Heterografts; D006801:Humans; D007577:JC Virus / Q000502:physiology*; D007968:Leukoencephalopathy, Progressive Multifocal / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000276:immunology* / Q000473:pathology; D018183:Transplantation Chimera / Q000276:immunology*; D014779:Virus Replication / Q000276:immunology*
D000957:Antigens, Viral, Tumor; D036022:Capsid Proteins; C062481:VP1 protein, polyomavirus