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Background: Multiple sclerosis (MS) is an important disease affecting young adults. Epidemiological studies indicate that this disease critically depends on environmental factors, including infectious agents. It appears that infections with a variety of neurotropic infectious agents can precipitate the stereotyped pathological tissue response. Experimental models in mice can mirror all aspects of neurodegenerative diseases such as MS: chronic immune activation in peripheral lymphoid organs, persistent inflammatory responses with activation/destruction of glia cells, demyelination, and axonal death. Infection with neurotropic mouse hepatitis virus (MHV) is well-suited to better understand the basic mechanisms underlying both acute virus-induced CNS pathologies and those factors that determine chronic disease. Our laboratory has established a reverse genetic technique with the cloning of full-length MHV genomes that facilitates the in vivo analysis of essential coronavirus-encoded pathogenicity factors. Furthermore, we have been able to assess the role of different dendritic cell subsets to counteract coronavirus-mediated disease.
Working hypothesis: In this project, we will work along the major hypothesis that the interplay between virally encoded pathogenicity factors and cellular immunoregulatory factors critically determines the outcome of MHV- mediated CNS disease.
Specific aims: The first aim of this study to analyze CNS tropism and pathogenicity of MHV mutant viruses that lack important immunostimulatory components, i.e. selected non-structural proteins (nsps). Mutants lacking a functional nsp1, or exhibiting point mutations in essentials domains within nsp3, and nsp14 have been generated in our laboratory. The second aim is the delineation of immunopathological mechanisms during MHV-induced demyelinating disease. To this end, spreading of the T helper cell response towards genuine CNS autoantigens (e.g. myelin oligodendrocyte protein, MOG) will be assess using TCR transgenics. Furthermore, the role of different professional antigen presenting cells in the initiation and maintenance of antiviral and autoantigen-specific T cell responses will be assessed in novel mouse models that permit the selective ablation of dendritic cells and/or macrophages. Finally, it is planned to assess the role of regulatory T cells in the course of chronic neurodegeneration following MHV infection. To this end, transgenic DEREG mice will be used that permit the depletion of these cells via injection of diphtheria toxin.
Potential significance: The work of coronavirus-encoded regulatory factors that impinge on the cellular tropism, the establishment of persistence within the CNS, and activation of innate and adaptive antiviral immune responses in the CNS, will deliver critical new knowledge on the immunopathological basis of MHV-mediated demyelinating disease. The combination of MHV-induced inflammatory CNS disease with novel transgenic models that facilitate modulation of self-antigen presentation or deletion of regulatory T cells will permit comprehensive studies on the immunopathological mechanisms of this MS-like disease.