Coronavirus-Induced Demyelination Occurs in the Presence of Virus-Specific Cytotoxic T Cells

Abstract

C57BI/6, but not BALB/c, mice infected with mouse hepatitis virus strain JHM (MHV-JHM) develop a late onset, symptomatic demyelinating encephalomyelitis. In this report, we characterized anti-viral cytotoxic T cells in the central nervous system and spleen during the acute and chronic stages of the MHV infection. The data show that C57BI/6 mice display a cytotoxic T cell (CTL) response to the surface (S) glycoprotein and this response can be demonstrated in lymphocytes isolated from the brains and spinal cords of mice both acutely and persistently infected with MHV-JHM. Thus, the anti-S CTL activity present in the central nervous system of chronically infected animals is not sufficient to prevent the demyelinating process. BALB/c mice have been shown previously to mount a CTL response against the nucleocapsid (N) protein (Stohlman et al., 1992). Since C57BI/6 mice do not mount a response to the N protein, the role of the N-specific response in preventing the late onset disease was assessed using B10.A(18R) mice, recombinant in the H-2 locus. These mice contain the d alleles of the D and L loci and exhibit a CTL response against the N protein. However, unlike the BALB/c mice, these animals develop the late onset symptomatic disease. These results suggest that the N-specific response is partially protective against the development of the demyelinating disease, but that additional factors are also likely to be involved.

The JHM strain of mouse hepatitis virus induces a spike protein-specific Db-restricted cytotoxic T cell response

“…Only CTL specific for the S protein were identified. Interestingly, little CTL activity was detected in spleen cells during acute infection and no activity was detected during chronic infection (Castro et al, 1994). This observation is consistent with previous analysis of the CTL response following CNS infection of BALB/c mice, which demonstrated no CTL specific for the N protein in splenic or cervical lymph node populations during acute CNS infection .…”

“…Using truncation and deletion variants of the S protein expressed by recombinant vaccinia virus (rVV), the CTL response was found to be restricted to a single epitope within the amino-terminal third of the protein (aa 510 518) containing the D b binding motif. All 24 CD8 + CTL lines analysed recognized the S protein in the context of D "°, consistent with the previous suggestion of a dominant CTL response in H-2 b mice (Castro et al, 1994). These data demonstrate that peripheral infection with JHMV induces a CTL response in H-2 b mice which appears to be restricted to a single Db-restricted epitope within the S protein.…”

“…In this report we confirm that CTL specific for the JHMV S protein are induced in H-2 b mice and that no CTL specific for either the M or N proteins are induced (Castro et al, 1994). In addition, no HE-specific or small membrane (sM)-specific CTL were detected.…”

“…However, CTL clones specific for an unidentified epitope, believed to be contained within a non-structural protein, were also identified . In contrast to BALB/c mice Stohlman et al, 1993), few JHMV-specific CTL were detected following peripheral infection of C57BL/6 (H-2 b) mice with JHMV (Castro et al, 1994). In addition, it has been suggested that CD4 + CTL predominate in this haplotype following infection with the related MHV-A59 strain due to reduced expression of MHC class I following infection (Heemskerk et al, 1995).…”

“…Although infection with MHV decreases host mRNA levels , translation of host mRNAs (Tahara et al, 1994) and MHC class I cell surface expression , sufficient class I molecules are expressed for CTL recognition of target cells infected with a variety of MHV strains, including MHV-A59 (Bergmann et al, 1993a). CD8 + CTL activity can be detected in the CNS during both acute and chronic JHMV infection of C57BL/6 mice (Castro et al, 1994). Specificity of these CTL was determined using target cells expressing the S, N and M proteins.…”