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Mouse hepatitis virus A59-induced demyelination can occur in the absence of CD8+ T cells
J L Gombold1, R M Sutherland, E Lavi
1Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia 19104-6076, USA.
Abstract:
Mouse hepatitis virus causes a chronic demyelinating disease in C57BL/6 mice. While early studies suggested demyelination is due to direct cytolytic effects of virus on oligodendrocytes, there is increasing evidence for the involvement of the immune system in the mechanism of demyelination. In this study we have asked whether demyelination can occur in the absence of functional MHC class I expression and CD8+ T cells. We infected transgenic mice lacking expression of beta 2 microglobulin (beta 2 M -/- mice) with MHV-A59. In beta 2M-/- mice, virus was much more lethal than in either of the parental strains used to produce the mice; furthermore, while clearance from the CNS did occur in beta 2M-/- mice, it was slower than in C57BL/6 mice. This is consistent with the importance of CD8+ cells in viral clearance. Because of the increased sensitivity of the beta 2M-/- mice to infection, only low levels of virus could be used to evaluate chronic disease. Even at these low levels, demyelination did occur in some animals. To compare infection in beta 2M-/- and C57BL/6 mice we used a higher dose of an attenuated variant of MHV-A59, C12. The attenuated variant induced less demyelination in C57BL/6 mice compared to wild type A59, but the levels observed were not significantly different from those seen in beta 2M-/- mice. Thus, MHV-induced demyelination can occur in some animals in the absence of MHC class I and CD8+ cells.
Insights
Mouse hepatitis virus (MHV) can cause demyelination even without MHC class I and CD8+ T cells. This suggests immune cells are not solely responsible for MHV-induced demyelination in mice.
Area of Science:
- Neuroimmunology
- Virology
- Immunology
Background:
- Mouse hepatitis virus (MHV) causes chronic demyelinating disease.
- Demyelination mechanisms are debated, with roles for direct viral effects and immune system involvement.
- MHC class I and CD8+ T cells are critical for viral clearance.
Purpose of the Study:
- To investigate if demyelination occurs without functional MHC class I expression and CD8+ T cells.
- To understand the role of CD8+ T cells in MHV-induced demyelination.
Main Methods:
- Infection of beta 2 microglobulin knockout (beta 2M-/-) mice with MHV-A59.
- Comparison of viral lethality, central nervous system (CNS) viral clearance, and demyelination levels between beta 2M-/- and C57BL/6 mice.
- Use of an attenuated MHV-A59 variant (C12) to assess demyelination in both mouse models.
Main Results:
- Beta 2M-/- mice exhibited increased susceptibility and slower viral clearance compared to C57BL/6 mice.
- Despite increased susceptibility, demyelination was observed in some beta 2M-/- mice at low viral doses.
- Similar levels of demyelination were observed in beta 2M-/- and C57BL/6 mice when infected with the attenuated MHV-C12 variant.
Conclusions:
- MHV-induced demyelination can occur independently of MHC class I expression and CD8+ T cells.
- CD8+ T cells play a role in viral clearance but are not essential for demyelination.
- The findings challenge the notion that immune-mediated damage by CD8+ T cells is the sole driver of MHV-induced demyelination.