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The infection of mouse by Theiler's virus: from genetics to immunology
P Monteyne1, J F Bureau, M Brahic
1Institut Pasteur, Unité des Virus Lents, CNRS, Paris, France.
Abstract:
Theiler's virus is a picornavirus of mouse which causes an acute encephalomyelitis followed by a persistent infection of the white matter of the spinal cord with chronic inflammation and demyelination. This late disease is studied as a model for multiple sclerosis. Inbred strains of mice differ in their susceptibility to persistent infection and demyelination. Resistant strains clear the infection after the acute encephalomyelitis. This observation is the basis of genetic studies which we used as a thread for this review. The H-2D locus has a major effect on susceptibility. The H-2Db gene is involved in a fast and intense CTL response which confers resistance. The Tcrb locus is also implicated, although there is no proof that the susceptibility gene in this region codes for the T-cell receptor. A complete screen of the genome uncovered the role of the Ifng locus and led to the demonstration that IFN-gamma limits viral spread in the white matter. The roles of NK cells and B cells in limiting the infection are discussed. CD4+ T cells participate both in protection against the infection and in demyelination. Finally, the effect of non-immune factors in resistance is illustrated by mice with mutations in the MBP or PLP gene.
Insights
Genetic factors influence Theiler's virus infection in mice, a model for multiple sclerosis. The H-2Db gene and interferon-gamma (IFN-γ) are key to resistance against persistent viral infection and demyelination.
Area of Science:
- Neuroimmunology
- Virology
- Genetics
Background:
- Theiler's virus infection in mice serves as a model for multiple sclerosis, exhibiting acute encephalomyelitis followed by chronic demyelination.
- Susceptibility to persistent infection and demyelination varies significantly among inbred mouse strains, with resistant strains clearing the virus post-acute phase.
Purpose of the Study:
- To review the genetic basis of resistance and susceptibility to Theiler's virus-induced demyelination.
- To explore the roles of various immune and non-immune factors in controlling viral persistence and disease progression.
Main Methods:
- Analysis of genetic studies focusing on mouse strains with differing susceptibility to Theiler's virus.
- Investigation of the impact of specific genetic loci (H-2D, Tcrb, Ifng) and immune cells (CTL, NK, B, CD4+ T cells) on viral clearance and demyelination.
Main Results:
- The H-2D locus, particularly the H-2Db gene, significantly influences susceptibility through a rapid cytotoxic T lymphocyte (CTL) response.
- Interferon-gamma (IFN-γ) limits viral spread in the white matter, while CD4+ T cells play dual roles in protection and pathology.
- Non-immune factors, such as mutations in myelin basic protein (MBP) or proteolipid protein (PLP) genes, also affect resistance.
Conclusions:
- Genetic control, particularly involving the H-2Db gene and IFN-γ, is crucial for resistance to Theiler's virus-induced demyelination.
- Immune cell populations, including CTLs, NK cells, B cells, and CD4+ T cells, contribute to the control of viral infection and the pathogenesis of demyelination.