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Published on: May 18, 2010
The importance of mouse models to define immunovirologic determinants of progressive multifocal leukoencephalopathy
Elizabeth L Frost1, Aron E Lukacher2
1Immunology and Molecular Pathogenesis Graduate Program, Emory University , Atlanta, GA , USA.
Abstract:
Progressive multifocal leukoencephalopathy (PML) is a severely debilitating and often fatal demyelinating disease of the central nervous system (CNS) in immunosuppressed individuals caused by JC polyomavirus (JCV), a ubiquitous human pathogen. Demyelination results from lytically infected oligodendrocytes, whose clearance is impaired in the setting of depressed JCV-specific T cell-mediated CNS surveillance. Although mutations in the viral capsid and genomic rearrangements in the viral non-coding region appear to set the stage for PML in the immunosuppressed population, mechanisms of demyelination and CNS antiviral immunity are poorly understood in large part due to absence of a tractable animal model that mimics PML neuropathology in humans. Early studies using mouse polyomavirus (MPyV) in T cell-deficient mice demonstrated productive viral replication in the CNS and demyelination; however, these findings were confounded by spinal cord compression by virus-induced vertebral bone tumors. Here, we review current literature regarding animal models of PML, focusing on current trends in antiviral T cell immunity in non-lymphoid organs, including the CNS. Advances in our understanding of polyomavirus lifecycles, viral and host determinants of persistent infection, and T cell-mediated immunity to viral infections in the CNS warrant revisiting polyomavirus CNS infection in the mouse as a bona fide animal model for JCV-PML.
Insights
Progressive multifocal leukoencephalopathy (PML) is a fatal CNS disease caused by JC polyomavirus (JCV). Revisiting mouse polyomavirus (MPyV) CNS infection may offer a viable model for studying PML and T cell immunity.
Area of Science:
- Neuroimmunology
- Virology
- Demyelinating Diseases
Background:
- Progressive multifocal leukoencephalopathy (PML) is a severe CNS demyelinating disease in immunosuppressed individuals, caused by JC polyomavirus (JCV).
- Impaired T cell surveillance of the CNS contributes to demyelination by JCV-infected oligodendrocytes.
- Current understanding of PML neuropathology and CNS antiviral immunity is limited by the lack of a suitable animal model.
Purpose of the Study:
- To review the literature on animal models for PML.
- To explore the potential of revisiting mouse polyomavirus (MPyV) CNS infection as a model for JCV-PML.
- To discuss advances in understanding T cell immunity in the CNS.
Main Methods:
- Literature review focusing on PML animal models and CNS antiviral T cell immunity.
- Analysis of historical studies using MPyV in T cell-deficient mice.
- Discussion of polyomavirus lifecycles and host-viral interactions.
Main Results:
- Previous MPyV studies in mice showed CNS replication and demyelination but were confounded by tumors.
- Current understanding of viral persistence and T cell-mediated CNS immunity has advanced.
- Revisiting MPyV CNS infection warrants consideration as a PML model.
Conclusions:
- Advances in virology and immunology support reconsidering MPyV as a PML model.
- A well-characterized MPyV CNS infection model could elucidate PML pathogenesis and CNS antiviral responses.
- This approach may improve understanding of JCV-PML and inform therapeutic strategies.
