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Updated: Aug 14, 2026
Two-photon Imaging of Cellular Dynamics in the Mouse Spinal Cord
Published on: February 22, 2015
STAT4- and STAT6-signaling molecules in a murine model of multiple sclerosis
Moses Rodriguez1, Laurie Zoecklein, Jeffrey D Gamez
1Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905, USA. rodriguez.moses@mayo.edu
Abstract:
Epidemiological studies suggest that an environmental factor (possibly a virus) acquired early in life may trigger multiple sclerosis (MS). The virus may remain dormant in the central nervous system but then becomes activated in adulthood. All existing models of MS are characterized by inflammation or demyelination that follows days after virus infection or antigen inoculation. While investigating the role of CD4+ T cell responses following Theiler's virus infection in mice deficient in STAT4 or STAT6, we discovered a model in which virus infection was followed by demyelination after a very prolonged incubation period. STAT4-/- mice were resistant to demyelination for 180 days after infection, but developed severe demyelination after this time point. Inflammatory cells and up-regulation of Class I and Class II MHC antigens characterized these lesions. Virus antigen was partially controlled during the early chronic phase of the infection even though viral RNA levels remained high throughout infection. Demyelination correlated with the appearance of virus antigen expression. Bone marrow reconstitution experiments indicated that the mechanism of the late onset demyelination was the result of the STAT4-/- immune system. Thus, virus infection of STAT4-/- mice results in a model that may allow for dissection of the immune events predisposing to late-onset demyelination in MS.
Insights
A novel mouse model reveals that STAT4 deficiency leads to a delayed onset of demyelination after Theiler
Area of Science:
- Immunology
- Neuroscience
- Virology
Background:
- Epidemiological studies suggest early-life environmental factors, potentially viral, may trigger multiple sclerosis (MS) later in life.
- Current MS models show rapid inflammation/demyelination post-infection, unlike the proposed delayed onset in humans.
- The role of STAT4 in immune responses and its potential link to delayed demyelination remains unclear.
Purpose of the Study:
- To investigate the role of STAT4 in T cell responses following Theiler's virus infection.
- To establish and characterize a novel mouse model for studying late-onset demyelination relevant to MS.
Main Methods:
- Infection of STAT4-deficient (STAT4-/-) and STAT6-deficient mice with Theiler's virus.
- Monitoring for demyelination, inflammation, viral RNA levels, and antigen expression over an extended period (180+ days).
- Bone marrow reconstitution experiments to determine the immune system's role in demyelination.
Main Results:
- STAT4-/- mice showed resistance to demyelination for 180 days post-infection, followed by severe demyelination.
- Lesions in STAT4-/- mice exhibited inflammatory cells and upregulated MHC Class I and II antigens.
- Demyelination correlated with virus antigen expression, despite high viral RNA levels throughout infection.
Conclusions:
- Theiler's virus infection in STAT4-/- mice provides a new model for late-onset demyelination.
- The STAT4-/- immune system is critical for the observed delayed demyelination.
- This model may help elucidate immune mechanisms underlying late-onset demyelination in multiple sclerosis.
