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Cellular reservoirs for coronavirus infection of the brain in beta2-microglobulin knockout mice
E Lavi1, J Das Sarma, S R Weiss
1Division of Neuropathology, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6085, USA.lavi@mail.med.upenn.edu
Abstract:
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 beta2-microglobulin 'knockout' (beta2M(-/-)) mice required 500-fold less virus and viral clearance was delayed as compared to infection of immunocompetent C57Bl/6 (B6) mice. To investigate the mechanism of the increased susceptibility of beta2M(-/-) mice to MHV-A59, we studied organ pathology and the distribution of viral antigen and RNA during acute and chronic infection. A59-infected beta2M(-/-) mice were more susceptible to acute encephalitis and hepatitis, but did not have increased susceptibility to demyelination. Viral antigen and RNA distribution in the brain was increased in microglia, lymphocytes, and small vessel endothelial cells while the distribution in neurons and glia was similar in beta2M(-/-) mice and B6 mice. Acute hepatitis and thymus cortical hypoplasia in beta2M(-/-) mice were delayed in onset but pathologic changes in these organs were similar to those in B6 mice. The low rate of demyelination in beta2M(-/-) mice was consistent with the low dose of the virus given. A less neurotropic virus MHV-2, caused increased parenchymal inflammation in beta2M(-/-) mice, but without demyelination. Thus, CD8+ cells were important for viral clearance from endothelial cells, microglia and inflammatory cells, but not from neuronal and glial cells. In addition, CD8+ cells played a role in preventing the spread of encephalitis.
Insights
Beta2-microglobulin knockout mice show increased susceptibility to mouse hepatitis virus (MHV) A59, leading to severe encephalitis and hepatitis. CD8+ T cells are crucial for clearing the virus from specific cells and preventing encephalitis spread.
Area of Science:
- Immunology
- Virology
- Neuroscience
Background:
- Mouse hepatitis virus (MHV) A59 serves as a model for multiple sclerosis, causing encephalitis, hepatitis, and demyelination.
- Beta2-microglobulin knockout (beta2M(-/-)) mice exhibit heightened susceptibility to MHV-A59, requiring significantly less virus for lethal infection and showing delayed viral clearance compared to immunocompetent mice.
Purpose of the Study:
- To elucidate the mechanisms underlying the increased susceptibility of beta2M(-/-) mice to MHV-A59 infection.
- To analyze organ pathology and viral antigen/RNA distribution in beta2M(-/-) mice during acute and chronic MHV-A59 infection.
Main Methods:
- Comparative analysis of organ pathology and viral distribution in MHV-A59 infected beta2M(-/-) and C57Bl/6 (B6) mice.
- Assessment of viral antigen and RNA distribution in various cell types within the brain, liver, and thymus.
- Infection studies using a less neurotropic MHV-2 strain to evaluate the role of CD8+ cells.
Main Results:
- Beta2M(-/-) mice displayed increased susceptibility to acute encephalitis and hepatitis, but not demyelination, following MHV-A59 infection.
- Viral antigen and RNA were more prevalent in microglia, lymphocytes, and endothelial cells of the brain in beta2M(-/-) mice.
- CD8+ T cells were essential for viral clearance from endothelial cells, microglia, and inflammatory cells, and played a role in limiting encephalitis spread, but not from neurons or glia.
Conclusions:
- The absence of beta2-microglobulin exacerbates MHV-A59 induced encephalitis and hepatitis, primarily due to altered viral distribution in specific immune and vascular cells.
- CD8+ T cell responses are critical for controlling MHV-A59 infection in peripheral tissues and preventing severe neurological disease, though their role in clearing the virus from neurons and glia is limited.