Cellular reservoirs for coronavirus infection of the brain in beta(2)-microglobulin knockout mice

Mouse hepatitis virus (MHV) A59 infection which causes acute encephalitis, hepatitis, and chronic demyelination, is one of the experimental models for multiple sclerosis. Previous studies showed that lethal infection of beta( 2)-microglobulin 'knockout' (beta(2)M(-/-)) mice required 500-fold less vir us and viral clearance was delayed as compared to infection of immunocompet ent C57Bl/6 (B6) mice. To investigate the mechanism of the increased suscep tibility of beta(2)M(-/-) mice to MHV-A59, we studied organ pathology and t he distribution of viral antigen and RNA during acute and chronic infection . A59-infected beta(2)M(-/-) mice were more susceptible to acute encephalit is and hepatitis, but did not have increased susceptibility to demyelinatio n. Viral antigen and RNA distribution in the brain was increased in microgl ia, lymphocytes, and small vessel endothelial cells while the distribution in neurons and glia was similar in beta(2)M(-/-) mice and B6 mice. Acute he patitis and thymus cortical hypoplasia in beta(2)M(-/-) mice were delayed i n onset but pathologic changes in these organs were similar to those in B6 mice. The low rate of demyelination in beta(2)M(-/-) mice was consistent wi th the low dose of the virus given. A less neurotropic virus MHV-2, caused increased parenchymal inflammation in beta(2)M(-/-) mice, but without demye lination. Thus, CD8+ cells were important for viral clearance from endothel ial cells, microglia and inflammatory cells, but not from neuronal and glia l cells. In addition, CD8+ cells played a role in preventing the spread of encephalitis.