The etiology and pathogenesis of multiple sclerosis and the post- infectious encephalopathies are not known. Treatment is generally ineffective. Virus infection and/or the generation of aberrant immune responses have been suspected to play a major role in the etiology of these entities. This proposal is directed at studying the interaction of virus with antiviral immune responses mounted by the host. Such events could lead to autoimmune phenomenon through the generation and/or expansion of self reactive cells within the central nervous system (CNS). In addition, direct viral interactions can contribute to CNS pathology. By comprehending the mechanisms how viruses interact with the immune system and target tissues to produce disease will provide valuable information applicable toward understanding CNS diseases in man and hopefully their eventual treatment and prevention. In this proposal experiments are planned to extend our initial observations examining homologies and cross-reacting immune responses between viral determinants and self constituents. In many instances these cross-reactions are interesting however the role in disease is unclear. Therefore, studies are purposed to investigate models to examine the biological relevance of the cross-reacting immune responses in actual disease induction. Two models will be studied in depth. First the role of antibodies which cross-react with virus and self components in initiating or enhancing CNS disease will be investigated. Second, employing vaccinia virus constructs having cDNA coding regions from myelin basic protein, proteolipid protein and myelin associated glycoprotein, mice will be infected to determine whether an autoimmune disease can be initiated by a virus carrying a known """"""""disease"""""""" inducing region. Further, the requirements for disease induction and whether such constructs can protect or modify an existing autoimmune disease will be pursued. In addition the direct viral effects on CNS disease as well as immune mediated contributions to demyelination will be examined. The model of Theiler's murine encephalomyelitis virus infection of mice will be utilized. This is a murine picornavirus that can produce a demyelinating disease in the appropriate mouse strains. Here experiments defining the role of virus versus immune mediated disease are proposed in immunocompromised mice. Reconstitution experiments are delineated to determine the relative role each may play in initiating and maintaining CNS injury. Additional experiments are planned to define whether immunologic responses can mediate viral clearance in the model system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS023162-08
Application #
3406391
Study Section
Experimental Virology Study Section (EVR)
Project Start
1986-08-01
Project End
1996-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
8
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Utah
Department
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Wang, L Y; Fujinami, R S (1997) Enhancement of EAE and induction of autoantibodies to T-cell epitopes in mice infected with a recombinant vaccinia virus encoding myelin proteolipid protein. J Neuroimmunol 75:75-83
Tsunoda, I; Fujinami, R S (1996) Two models for multiple sclerosis: experimental allergic encephalomyelitis and Theiler's murine encephalomyelitis virus. J Neuropathol Exp Neurol 55:673-86
Barnett, L A; Whitton, J L; Wang, L Y et al. (1996) Virus encoding an encephalitogenic peptide protects mice from experimental allergic encephalomyelitis. J Neuroimmunol 64:163-73
Kurtz, C I; Sun, X M; Fujinami, R S (1995) B-lymphocyte requirement for vaccine-mediated protection from Theiler's murine encephalomyelitis virus-induced central nervous system disease. J Virol 69:5152-5
Kurtz, C I; Sun, X M; Fujinami, R S (1995) Protection of SJL/J mice from demyelinating disease mediated by Theiler's murine encephalomyelitis virus. Microb Pathog 18:11-27
Kurtz, C I; McCarron, R M; Spatz, M et al. (1994) Characterization of a murine central nervous system-derived cell line: infectability and presentation of viral antigen. J Neuroimmunol 51:35-43
Wada, Y; Pierce, M L; Fujinami, R S (1994) Importance of amino acid 101 within capsid protein VP1 for modulation of Theiler's virus-induced disease. J Virol 68:1219-23
Barnett, L A; Whitton, J L; Wada, Y et al. (1993) Enhancement of autoimmune disease using recombinant vaccinia virus encoding myelin proteolipid protein. J Neuroimmunol 44:15-25
Wada, Y; Fujinami, R S (1993) Viral infection and dissemination through the olfactory pathway and the limbic system by Theiler's virus. Am J Pathol 143:221-9
Yamada, M; Zurbriggen, A; Oldstone, M B et al. (1991) Common immunologic determinant between human immunodeficiency virus type 1 gp41 and astrocytes. J Virol 65:1370-6

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