The JHM strain of mouse hepatitis virus (JHMV) produces an acute encephalitis accompanied by demyelination. Survivors have chronic demyelination associated with persistent viral RNA and antigen to the central nervous system (CNS). Persistence is not associated with infectious virus and no data is yet available to suggest a mechanism for the persistence of a 31 Kb viral genome. The strength of the immune response during acute infection is a critical determinant in establishing chronic disease; however, its relevance during persistence has not been established. This proposal addresses two interrelated aspects of JHMV- induced chronic disease: potential role of viral evolution leading to attenuated replication and the role of CD8+ T cell activation for disease outcome and memory. Our data indicate that genetic mutations associated with CNS persistence are not the result of immune-driven events. Therefore, mutations associated with persistence will be tested in three areas of the viral genome involved in replication: the nucleocapsid (N) and envelope (E) proteins and the leader RNA sequence. N protein is involved in transcription and translation. Defects in any of these could result in attenuated replication and persistence.
The second aim examines the role of CNS cells as antigen-presenting cells of virus clearance from the CNS. However, their inability to provide sterile immunity indicates a suboptimal effector response. Characterization of the relative frequencies and phenotype associated with the cytolytic effector phase found exclusively in the CNS will provide insights into the development of effector function relative to viral replication.
The third aim explores the specificities of unique memory CTL populations contained within the CNS. CTL represent in the CNS during persistent infection appear to loose the ability to recognize potential variations in the immunodominant epitope. The selection of CTL subsets exhibiting enhanced selectivity into the memory population will be monitored by phenotypic characterization and functional assays. These experiments will provide evidence for a potential effector function in response to residual antigen during viral persistence. This proposal examines the critical question of how the CNS regulated CTL induction, activation and memory responses during a parenchymal infection that results in persistent infection and ongoing chronic demyelination.
|Kapil, Parul; Butchi, Niranjan B; Stohlman, Stephen A et al. (2012) Oligodendroglia are limited in type I interferon induction and responsiveness in vivo. Glia 60:1555-66|
|Savarin, Carine; Stohlman, Stephen A; Rietsch, Anna M et al. (2011) MMP9 deficiency does not decrease blood-brain barrier disruption, but increases astrocyte MMP3 expression during viral encephalomyelitis. Glia 59:1770-81|
|Savarin, Carine; Stohlman, Stephen A; Atkinson, Roscoe et al. (2010) Monocytes regulate T cell migration through the glia limitans during acute viral encephalitis. J Virol 84:4878-88|
|Phares, Timothy W; Stohlman, Stephen A; Hinton, David R et al. (2010) Enhanced antiviral T cell function in the absence of B7-H1 is insufficient to prevent persistence but exacerbates axonal bystander damage during viral encephalomyelitis. J Immunol 185:5607-18|
|Phares, Timothy W; Ramakrishna, Chandran; Parra, Gabriel I et al. (2009) Target-dependent B7-H1 regulation contributes to clearance of central nervous system infection and dampens morbidity. J Immunol 182:5430-8|
|Zuo, Jun; Stohlman, Stephen A; Parra, Gabriel I et al. (2009) IL-15 independent maintenance of virus-specific CD8(+) T cells in the CNS during chronic infection. J Neuroimmunol 207:32-8|
|Savarin, Carine; Bergmann, Cornelia C (2008) Neuroimmunology of central nervous system viral infections: the cells, molecules and mechanisms involved. Curr Opin Pharmacol 8:472-9|
|Stohlman, S A; Hinton, D R (2001) Viral induced demyelination. Brain Pathol 11:92-106|
|Stohlman, S A; Bergmann, C; Cua, D et al. (1994) Location of antibody epitopes within the mouse hepatitis virus nucleocapsid protein. Virology 202:146-53|
|Strong, R K; Penny, D M; Feldman, R M et al. (1994) Engineering and expression of a secreted murine TCR with reduced N-linked glycosylation. J Immunol 153:4111-21|