The etiology of the human demyelinating disease, multiple sclerosis (MS), is not known. Current hypotheses propose that the disease is autoimmune, viral or both in nature. Thus far, no autoimmune animal model perfectly mimics the clinical and pathological features of patients with MS. Similarly, various immunological treatments which ameliorate a central nervous system (CNS) autoimmune disease model, experimental allergic encephalomyelitis (EAE) when conducted with MS patients, for the most part have not modulated the disease. Although, one treatment which lessens EAE does alter the course of MS, that being interferon beta. Thus, there is precedence for an autoimmune based model. However, there is equally convincing evidence that there is viral involvement in human CNS demyelinating disease. For example, the next most common naturally occurring demyelinating diseases besides MS involves virus infections. The post-viral encephalomyelopathies such as post measles virus encephalomyelopathy consists of infection with measles virus followed by; clinical symptoms of CNS involvement, the presence of increased numbers of myelin basic protein specific T cells and areas of demyelination. Most of these individuals recover, but approximately 10% of those involved have residual effects. In addition, virus infections have also been associated with either the initiation or exacerbations observed in MS. Thus, while the etiology of MS is unknown there is good evidence that viruses play a role in human demyelinating disease and possibly MS. Since experiments with MS subjects in most instances are not ethical, animal-virus infection models which mimic many of the features of MS, offer a rational approach. We have been using the Theiler's murine encephalomyelitis virus (TMEV) infection of SJL/J mice as a model for human demyelinating diseases. This is a naturally occurring infection of mice and the mouse is the natural host for the virus. The goals and aims of this proposal are to study the interactions of the virus and the host and how this leads to CNS demyelinating disease.
The first aim i s to determine the structural sites which are important for viral tropism and persistence in the context of pathogenesis.
The second aim i s to explore the immunologic contributions for protection from CNS disease and viral clearance.
The third aim i s to determine the cellular receptors on CNS and non-CNS cell-types which may be involved in viral tropism and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034497-04
Application #
2714573
Study Section
Neurology C Study Section (NEUC)
Program Officer
Kerza-Kwiatecki, a P
Project Start
1995-08-01
Project End
2000-05-31
Budget Start
1998-06-01
Budget End
2000-05-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Utah
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Tsunoda, Ikuo; Libbey, Jane E; Fujinami, Robert S (2012) Immunization with structural and non-structural proteins of Theiler's murine encephalomyelitis virus alters demyelinating disease. J Neurovirol 18:127-37
Libbey, Jane E; Cusick, Matthew F; Tsunoda, Ikuo et al. (2012) Antiviral CD8? T cells cause an experimental autoimmune encephalomyelitis-like disease in naive mice. J Neurovirol 18:45-54
Tsunoda, Ikuo; Tanaka, Tomoko; Taniguchi, Masaru et al. (2009) Contrasting roles for Valpha14+ natural killer T cells in a viral model for multiple sclerosis. J Neurovirol 15:90-8
Tsunoda, Ikuo; Libbey, Jane E; Fujinami, Robert S (2009) Theiler's murine encephalomyelitis virus attachment to the gastrointestinal tract is associated with sialic acid binding. J Neurovirol 15:81-9
Tsunoda, Ikuo; Tanaka, Tomoko; Fujinami, Robert S (2008) Regulatory role of CD1d in neurotropic virus infection. J Virol 82:10279-89
Tsunoda, Ikuo; Tanaka, Tomoko; Terry, Emily Jane et al. (2007) Contrasting roles for axonal degeneration in an autoimmune versus viral model of multiple sclerosis: When can axonal injury be beneficial? Am J Pathol 170:214-26
Tsunoda, Ikuo; Libbey, Jane E; Fujinami, Robert S (2007) TGF-beta1 suppresses T cell infiltration and VP2 puff B mutation enhances apoptosis in acute polioencephalitis induced by Theiler's virus. J Neuroimmunol 190:80-9
Tsunoda, Ikuo; Tanaka, Tomoko; Saijoh, Yukio et al. (2007) Targeting inflammatory demyelinating lesions to sites of Wallerian degeneration. Am J Pathol 171:1563-75
Libbey, Jane E; Tsunoda, Ikuo; Whitton, J Lindsay et al. (2007) Infectious RNA isolated from the spinal cords of mice chronically infected with Theiler's murine encephalomyelitis virus. J Virol 81:3009-11
Carlson, Noel G; Hill, Kenneth E; Tsunoda, Ikuo et al. (2006) The pathologic role for COX-2 in apoptotic oligodendrocytes in virus induced demyelinating disease: implications for multiple sclerosis. J Neuroimmunol 174:21-31

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