Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease in mice provides a highly relevant experimental animal model for multiple sclerosis because infection is in its natural host that is chronic for many months, influenced by major histocompatibility complex genetic alleles, includes both CD4+ and CD8+ T-cells in macrophage-rich lesions, and is a macrophage-rich immunopathology. TMEV-induced demyelination is primarily immune-mediated via virus-specific immune responses that lead to production of proinflammatory Th1 cytokines IFN? and TNF? as well as myelin protein epitope T cell responses. Reports of both T and B cell responses to myelin protein epitopes have led to the notion that autoimmunity amplifies this virus-induced immunopathology after day 60 pi when these autoimmune responses are observed. Moreover, it has recently even been argued that TMEV causes a chronic T cell-mediated autoimmune demyelinating disease triggered via epitope spreading with no apparent role for viral persistence in chronic demyelination. The possibility that autoimmunity evolves in a viral model of multiple sclerosis is appealing because it supports the widespread belief that multiple sclerosis is an autoimmune disease triggered by a virus infection. We hypothesize that these chronic "autoimmune responses" depend on persistent viral infection and are not self-sustaining in the absence of virus. A test of whether chronic TMEV-induced demyelination is autoimmune in the absence of viral persistence is to show a sustained virological response with antiviral treatment yet demonstrate continuous T cell responses to immunodominant myelin protein epitopes (epitope spreading), decreased T regulatory cells, progression of demyelination and loss of motor function. However, if virus- driven, T cell responses to myelin epitope should decrease (loss of epitope spreading), T regulatory cells should increase, demyelination should resolve or be slowed, and motor function should be restored with the absence of or with a lower viral burden. These and other approaches in this application seeks to gain a more complete understanding of host and viral dynamics of Theiler's murine encephalomyelitis virus infection, viral persistence and demyelination by using state-of-the art experimental approaches.

Public Health Relevance

Theiler's murine encephalomyelitis virus-induced demyelinating disease in mice provides a highly relevant experimental animal model for multiple sclerosis because infection is in its natural host, chronic for many months, influenced by major histocompatibility complex genetic alleles, contains both CD4+ and CD8+ T-cells in macrophage-rich lesions, and is a virus-induced immunopathology. Analysis of this viral model promises to provide a better understanding of the pathogenesis of MS, and perturbations such as macrophage depletion and antiviral treatment should elucidate the extent of the role of autoimmunity in demyelination.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS077755-03
Application #
8608610
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Wong, May
Project Start
2012-02-15
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
3
Fiscal Year
2014
Total Cost
$314,016
Indirect Cost
$117,141
Name
University of Illinois at Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Oberste, M Steven; Lipton, Howard L (2014) Global polio perspective. Neurology 82:1831-2
Jubelt, Burk; Lipton, Howard L (2014) Enterovirus/picornavirus infections. Handb Clin Neurol 123:379-416