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Departments of
*
Neurology,
Molecular Microbiology and Immunology, and
Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033; and
§
Departments of Neurology and Medical Microbiology, University of Wisconsin and William S. Middleton Veterans Hospital, Madison, WI 53792
Acute and chronic demyelination are hallmarks of CNS infection by
the neurotropic JHM strain of mouse hepatitis virus. Although
infectious virus is cleared by CD8+ T cells, both viral RNA
and activated CD8+ T cells remain in the CNS during
persistence potentially contributing to pathology. To dissociate immune
from virus-mediated determinants initiating and maintaining
demyelinating disease, mice were infected with two attenuated viral
variants differing in a hypervariable region of the spike protein.
Despite similar viral replication and tropism, one infection was marked
by extensive demyelination and paralysis, whereas the other resulted in
no clinical symptoms and minimal neuropathology. Mononuclear cells from
either infected brain exhibited virus specific ex vivo cytolytic
activity, which was rapidly lost during viral clearance. As revealed by
class I tetramer technology the paralytic variant was superior in
inducing specific CD8+ T cells during the acute disease.
However, after infectious virus was cleared, twice as many
virus-specific IFN-
-secreting CD8+ T cells were
recovered from the brains of asymptomatic mice compared with mice
undergoing demyelination, suggesting that IFN- ameliorates rather
than perpetuates JHM strain of mouse hepatitis virus-induced
demyelination. The present data thus indicate that in immunocompetent
mice, effector CD8+ T cells control infection without
mediating either clinical disease or demyelination. In contrast,
demyelination correlated with early and sustained infection of the
spinal cord. Rapid viral spread, attributed to determinants within the
spike protein and possibly perpetuated by suboptimal CD8+ T
cell effector function, thus ultimately leads to the process of
immune-mediated demyelination.
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