CD8+ T-cell epitopes within the surface glycoprotein of a neurotropic coronavirus and correlation with pathogenicity

Abstract

CD8 ؉ T cells with cytotoxic activity against the surface glycoprotein (S) of mouse hepatitis virus, strain JHM, have been identified in the central nervous system (CNS) of both acutely and chronically infected C57BL/6 mice. In this report, two specific epitopes recognized by these CNS-derived cells were identified, using a panel of peptides chosen because they conformed to the allele-specific binding motif for MHC class I H-2K b and H-2D b. The active peptides encompassed residues 510 to 518 (CSLWNGPHL, H-2D b) and 598 to 605 (RCQIFANI, H-2K b). Both epitopes are located within the region of the S protein previously shown to be prone to deletion after passage in animals. These deleted strains are generally less neurovirulent than the wild-type virus but still are able to cause demyelination. Since C57BL/6 mice become persistently infected more commonly than many other strains of mice, these data are consistent with a role for CD8 ؉ T-cell escape mutants in the pathogenesis of the demyelinating disease. This is the first report of CD8 ؉ T-cell epitope localization within the S protein, the protein most strongly implicated thus far in pathogenesis in the host.

Vaccines to prevent severe acute respiratory syndrome coronavirus-induced disease

“…Both humoral and T-cell-mediated responses to animal coronaviruses may exacerbate disease or cause new health problems . T-cell responses have been implicated in the demyelinization of the brain and spinal cord following infection with neurotropic MHV (Castro and Perlman, 1995;Wu et al, 2001), a group 2 coronavirus like SARS-CoV. Adverse humoral responses to another group 2 coronavirus, bovine coronavirus (BCoV), have also been linked to the development of "shipping fever" in cattle (O'Connor et al, 2001).…”

Identification of novel functional regions within the spike glycoprotein of MHV-A59 based on a bioinformatics approach

“…Although the multifunctional protein N contributes to the pathogenic outcome of coronavirus infection (Cowley et al, 2010), the MHV S protein plays a major role in the pathogenesis since it recognizes and binds the cellular receptor for the virus, Ceacam1a, mediates cell entry by inducing fusion of viral and cell membranes, subsequently facilitates virus spread to other cells by inducing cell to cell fusion (syncytium formation) at late times in infection when the S protein is abundantly present on the plasma membrane of infected cells (Dveksler et al, 1991), and recently it was found to regulate the intracellular transport of the viral genome from the cell surface to the ER (Zhu et al, 2009). S is also a major target of the host immune response, eliciting neutralizing antibodies and CD8+ cytotoxic T cell responses (Castro and Perlman, 1995).…”

Selection of and evasion from cytotoxic T cell responses in the central nervous system

“…In B6 mice, two MHV-specific epitopes are recognized. Cytotoxicity assays using CNS-derived lymphocytes from mice with acute encephalitis, directly ex vivo (Castro and Perlman, 1995), and limiting dilution assays using splenocytes harvested from mice intraperitoneally immunized with MHV , suggested, in both cases, that the two epitopes were recognized by similar numbers of CD8 T cells. More recent measurements, using MHC class I peptide/tetramers to detect antigen-specific cells or methods to detect interferon-~ production after stimulation with peptide, confirmed 234 STANLEY PERLMAN AND GREGORY F. WU these results (unpublished observations).…”

“…CTL escape mutations were detected in all mice that developed clinical disease several weeks postinfection in this model. In B6 mice, two CD8 T cell epitopes, encompassing residues 510-518 (S-510-518) (H-2Db-restricted) and 598-605 (S-598-605 (H-2Kb-restricted), of the S glycoprotein are recognized (Bergmann et al, 1996;Castro and Perlman, 1995). These two epitopes are located within a region of the protein that is prone to both mutation and deletion (termed the "hypervariable region") (Banner, Keck, and Lai, 1990;Parker, Gallagher, and Buchmeier, 1989).…”