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Published on: November 1, 2011
Genetics of susceptibility to Theiler's virus infection
1Institut Pasteur, Unité des Virus Lents, Paris, France. mbrahic@pasteur.fr
Abstract:
Theiler's virus is a picornavirus of mouse which causes an acute encephalomyelitis followed by a persistent infection of the white matter resulting in chronic inflammation and demyelination. This disease has been studied as a model for multiple sclerosis. Inbred strains of mice are either resistant--they clear the infection after the acute encephalomyelitis--or susceptible to persistent infection and demyelination. Susceptibility is a polygenic trait which has been analyzed using methods of association with "candidate" genes, and linkage analysis after a complete genome scan. The H-2Db gene is responsible for an efficient CTL response which makes some strains resistant. Non H-2 genes responsible for the susceptibility of other strains have been mapped by linkage analysis to the lfng and, possibly, the Mbp loci. The analysis of a set of congenic mice ruled out the possibility that the relevant gene codes for interferon gamma, and showed that the region around lfng probably contains two susceptibility genes. The analysis of mutant mice showed further that the Mbp gene, which codes for the myelin basic protein, has a major effect on viral persistence.
Insights
Theiler's virus infection in mice, a model for multiple sclerosis, reveals genetic factors influencing persistent demyelination. Key genes like H-2Db, lfng, and Mbp (myelin basic protein) control susceptibility and viral persistence.
Area of Science:
- Neuroimmunology
- Virology
- Genetics
Background:
- Theiler's virus infection in mice serves as a model for multiple sclerosis (MS).
- Mouse strains exhibit varying susceptibility to persistent infection, chronic inflammation, and demyelination.
- Genetic factors play a crucial role in determining disease outcome.
Purpose of the Study:
- To identify genetic loci controlling susceptibility to Theiler's virus-induced demyelination.
- To elucidate the roles of specific genes in viral persistence and immune response.
Main Methods:
- Genome-wide linkage analysis and association studies in inbred and congenic mouse strains.
- Analysis of mutant mice to assess gene function.
- Investigated candidate genes including H-2Db, interferon gamma, lfng, and Mbp.
Main Results:
- The H-2Db gene confers resistance through an efficient cytotoxic T lymphocyte (CTL) response.
- Non-H-2 genes, mapped to the lfng and Mbp loci, contribute to susceptibility.
- The Mbp gene (myelin basic protein) significantly impacts viral persistence.
Conclusions:
- Susceptibility to Theiler's virus-induced demyelination is a polygenic trait.
- Specific genetic loci, including lfng and Mbp, are critical for disease progression.
- Understanding these genetic factors provides insights into MS pathogenesis.
