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The shiverer mutation affects the persistence of Theiler's virus in the central nervous system
F Bihl1, C Pena-Rossi, J L Guénet
1Unité des Virus Lents (URA 1157 CNRS), Institut Pasteur, Paris, France.
Abstract:
Theiler's virus persists in the white matter of the spinal cord of genetically susceptible mice and causes primary demyelination. The virus persists in macrophages/microglial cells, but also in oligodendrocytes, the myelin-forming cells. Susceptibility/resistance to this chronic infection has been mapped to several loci including one tentatively located in the telomeric region of chromosome 18, close to the myelin basic protein locus (Mbp locus). To determine if the MBP gene influences viral persistence, we inoculated C3H mice bearing the shiverer mutation, a 20-kb deletion in the gene. Whereas control C3H mice were of intermediate susceptibility, C3H mice heterozygous for the mutation were very susceptible, and those homozygous for the mutation were completely resistant. This resistance was not immune mediated. Furthermore, C3H/101H mice homozygous for a point mutation in the gene coding for the proteolipid protein of myelin, the rumpshaker mutation, were resistant. These results strongly support the view that oligodendrocytes are a necessary viral target for the establishment of a persistent infection by Theiler's virus.
Insights
Theiler's virus persistence and demyelination depend on oligodendrocytes. Genetic mutations affecting myelin basic protein or proteolipid protein confer resistance to Theiler's virus infection in mice.
Area of Science:
- Neuroimmunology
- Virology
- Genetics
Background:
- Theiler's virus causes chronic demyelination in mouse spinal cord white matter.
- Viral persistence occurs in macrophages/microglia and oligodendrocytes, the myelin-forming cells.
- Genetic susceptibility to infection is linked to chromosome 18, near the myelin basic protein (Mbp) locus.
Purpose of the Study:
- To investigate the role of the myelin basic protein (MBP) gene in Theiler's virus persistence.
- To determine if mutations in myelin genes affect viral susceptibility and demyelination.
Main Methods:
- Inoculation of C3H mice with varying genotypes of the shiverer mutation (affecting MBP) with Theiler's virus.
- Assessment of viral susceptibility and resistance in mice homozygous and heterozygous for the shiverer mutation.
- Analysis of Theiler's virus infection in C3H/101H mice with the rumpshaker mutation (affecting proteolipid protein).
Main Results:
- C3H mice heterozygous for the shiverer mutation were highly susceptible to Theiler's virus.
- C3H mice homozygous for the shiverer mutation were completely resistant to infection.
- Mice homozygous for the rumpshaker mutation were also resistant, indicating resistance was not immune-mediated.
- Oligodendrocytes are essential viral targets for establishing persistent Theiler's virus infection.
Conclusions:
- Oligodendrocytes are critical for Theiler's virus persistence.
- The myelin basic protein and proteolipid protein genes play a significant role in determining susceptibility to Theiler's virus infection.
- Genetic factors influencing myelin integrity directly impact viral tropism and persistence.