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Role of CTL mutants in demyelination induced by mouse hepatitis virus, strain JHM
Abstract:
Mouse hepatitis virus, strain JHM (MHV-JHM) is a well described cause of demyelination. C57B1/6 (B6) mice infected at the suckling stage in the presence of protective antibodies remain asymptomatic initially but later develop clinical disease (hindlimb paralysis). Infectious virus can be isolated from these mice. Recently, two MHV-specific target epitopes for cytotoxic CD8 T cells have been identified in B6 mice. Our results show that in all mice with hindlimb paralysis, mutations can be detected in the RNA encoding the immunodominant of the two epitopes. These mutations result in a loss of recognition by MHV-specific cytotoxic T cells. These changes are not detected, for the most part, in mice that remain asymptomatic nor in mice with acute encephalitis. These results suggest that the development of CTL escape mutants is necessary for hindlimb paralysis to develop in this model.
Insights
Mutations in viral RNA allow Mouse Hepatitis Virus (MHV-JHM) to evade cytotoxic T cells, leading to hindlimb paralysis in C57B1/6 mice. This viral immune escape is crucial for disease development.
Area of Science:
- Virology
- Immunology
- Neuroscience
Background:
- Mouse hepatitis virus, strain JHM (MHV-JHM), is a known cause of demyelination.
- Infection in suckling C57B1/6 (B6) mice with protective antibodies can lead to delayed hindlimb paralysis despite initial asymptomatic periods.
Purpose of the Study:
- To investigate the role of viral mutations in the development of hindlimb paralysis in MHV-JHM infected B6 mice.
- To determine if cytotoxic T cell (CTL) escape mutants are associated with clinical disease.
Main Methods:
- Analysis of viral RNA sequences from MHV-JHM infected B6 mice exhibiting different clinical outcomes (asymptomatic, hindlimb paralysis, acute encephalitis).
- Assessment of MHV-specific CTL recognition of viral epitopes.
- Correlation of viral mutations with the presence and severity of neurological disease.
Main Results:
- Mice developing hindlimb paralysis showed mutations in the immunodominant MHV-JHM epitope targeted by CD8 T cells.
- These mutations resulted in a loss of recognition by MHV-specific CTLs.
- Such mutations were largely absent in asymptomatic mice and those with acute encephalitis.
Conclusions:
- The development of CTL escape mutants is a necessary event for the onset of hindlimb paralysis in this MHV-JHM mouse model.
- Viral immune evasion strategies play a critical role in the pathogenesis of demyelinating disease.