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Molecular pathogenesis of Theiler's murine encephalomyelitis virus-induced demyelinating disease in mice
1Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston, Ill., USA. hllipton@merle.acns.nwu.edu
Abstract:
After an acute phase of virus growth in neurons (e.g. anterior horn cells), Theiler's murine encephalomyelitis virus (TMEV) persists as a chronic productive infection, largely in macrophages in the CNS white matter. TMEV replication in macrophages is highly restricted, probably as the result of host cell factors. The preponderance of evidence indicates that TMEV persistence leads to immunopathologic damage of myelin, mediated by major histocompatibility class II-restricted Th1 lymphocytes directed at a virus epitope(s) rather than host neuroantigens at least early in the infection. Analysis of TMEV recombinant and mutant viruses suggests that persistence requires a specific capsid conformation involving the VP2 puff and VP1 loops, which may influence persistence through virion receptor binding or attachment to host cells, e.g. macrophages.
Insights
Theiler
Area of Science:
- Neuroimmunology
- Virology
- Molecular Biology
Background:
- Theiler's murine encephalomyelitis virus (TMEV) establishes chronic infection in the central nervous system (CNS), primarily in macrophages.
- Viral replication in macrophages is restricted, suggesting host cell factor involvement.
- TMEV persistence is linked to immunopathologic damage of myelin.
Purpose of the Study:
- To investigate the mechanisms of TMEV persistence in the CNS.
- To identify viral factors contributing to chronic infection and immunopathology.
Main Methods:
- Analysis of TMEV recombinant and mutant viruses.
- Study of viral capsid conformation and its role in persistence.
Main Results:
- TMEV persistence involves a specific capsid conformation, particularly the VP2 puff and VP1 loops.
- This capsid structure may mediate virion attachment to host cells like macrophages.
- Immune-mediated myelin damage is driven by Th1 lymphocytes targeting viral epitopes.
Conclusions:
- Viral capsid conformation is critical for TMEV persistence in macrophages.
- Understanding these viral-host interactions can inform strategies against chronic viral infections and associated neuroinflammation.