Cellular Reservoirs for Coronavirus Infection of the Brain in β₂-Microglobulin Knockout Mice

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 β₂-microglobulin ‘knockout’ (β₂M(–/–)) 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 β₂M(–/–) mice to MHV-A59, we studied organ pathology and the distribution of viral antigen and RNA during acute and chronic infection. A59-infected β₂M(–/–) 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 β₂M(–/–) mice and B6 mice. Acute hepatitis and thymus cortical hypoplasia in β₂M(–/–) mice were delayed in onset but pathologic changes in these organs were similar to those in B6 mice. The low rate of demyelination in β₂M(–/–) mice was consistent with the low dose of the virus given. A less neurotropic virus MHV-2, caused increased parenchymal inflammation in β₂M(–/–) 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.

CD8-deficient SJL mice display enhanced susceptibility to Theiler's virus infection and increased demyelinating pathology

“…It is possible, then, that in the resistant C57BL/6 strain, where virus is cleared rapidly, that the predominant response is Tc1 in nature. This idea is supported by data indicating that C57BL/6-perforin KO mice are able to be persistently infected with TMEV (Pena-Rossi et al, 1998), and that the absence of CD8 C T cells leads to viral titers that are dramatically increased (Figure 4) (Fiette et al, 1993;Pullen et al, 1993;Rodriguez et al, 1993;Rivera-Quinones et al, 1998;Lavi et al, 1999). This would be in contrast to the susceptible SJL/J strain where the predominant response may be Tc2 in nature, and/or minimally a weak Tc1, and the initial viremia is controlled, but not cleared.…”

“…However, as the majority of these studies were conducted using mice on a resistant genetic background (C57BL/6 and 129/J), in this study we sought to determine the outcome of the TMEV-IDD disease phenotype in the absence of CD8 C T cells in the highly susceptible SJL/J mice that were de cient in the expression of¯2M. Previous reports examining the effects of this mutation or the MHC class I knockout counterpart have provided evidence that the absence of CD8 C T cells on the resistant background leads to the establishment of chronic demyelination with or without clinical signs, extensive CNS in ltrate, and high viral titers, leading one to conclude that the primary role of these cells is in protection and regulation of disease (Fiette et al, 1993;Pullen et al, 1993;Rodriguez et al, 1993;Rivera-Quinones et al, 1998;Lavi et al, 1999). The current results support this central role for CD8 C T cells, with the secondary conclusion that CD4 C effector T cells are suf cient to mediate disease pathogenesis.…”

Expression of Neutral Glycosphingolipids in the Brain, Lymphoid Organs and Lungs of Mice Lacking β₂-Microglobulin

“…␤ 2 M-/-mice are known to have cellular reservoirs for coronavirus infection of the brain [13] . Our fi nding of increased Gb4 in the ␤ 2 M-/-brain may have implications for verotoxin and parvovirus B19 infections since Gb4 is described as their receptor [14,15] .…”

The Influence of Platelet-Derived Growth Factor and Fibroblast Growth Factor 2 on Oligodendrocyte Development and Remyelination

“…After virus injection, numerous cell types become infected including oligodendrocytes, astrocytes, neurons, macrophages, endothelial cells, hepatocytes, and others (Weiner, 1973;Lavi et al, 1987, Stohlman et al, 1995Lavi et al, 1999;Navas et al, 2001; reviewed in Matthews and Paterson, 2002). The first detectable immune response to MHV-A59 infection is the presence of anti-viral IgM antibodies at 6 days post infection (dpi; Stohlman et al, 1995) with CD8+ and CD4+ T cells peaking at 7 dpi and 9 dpi respectively (Williamson et al, 1991).…”