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Melanoma differentiation-associated gene 5 is critical for protection against Theiler's virus-induced demyelinating
Young-Hee Jin1, Seung Jae Kim, Eui Young So
1Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, Illinois, USA.
Abstract:
Infection of dendritic and glial cells with Theiler's murine encephalomyelitis virus (TMEV) induces various cytokines via Toll-like receptor- and melanoma differentiation-associated gene 5 (MDA5)-dependent pathways. However, the involvement and role of MDA5 in cytokine gene activation and the pathogenesis of TMEV-induced demyelinating disease are largely unknown. In this study, we demonstrate that MDA5 plays a critical role in the production of TMEV-induced alpha interferon (IFN-α) during early viral infection and in protection against the development of virus-induced demyelinating disease. Our results indicate that MDA5-deficient 129SvJ mice display significantly higher viral loads and apparent demyelinating lesions in the central nerve system (CNS) accompanied by clinical symptoms compared with wild-type 129SvJ mice. During acute viral infection, MDA5-deficient mice produced elevated levels of chemokines, consistent with increased cellular infiltration, but reduced levels of IFN-α, known to control T cell responses and cellular infiltration. Additional studies with isolated CNS glial cells from these mice suggest that cells from MDA5-deficient mice are severely compromised in the production of IFN-α upon viral infection, which results in increased cellular infiltration and viral loads in the CNS. Despite inadequate stimulation, the overall T cell responses to the viral determinants were significantly elevated in MDA5-deficient mice, reflecting the increased cellular infiltration. Therefore, the lack of MDA5-mediated IFN-α production may facilitate a massive viral load and elevated cellular infiltration in the CNS during early viral infection, leading to the pathogenesis of demyelinating disease.
Insights
Melanoma differentiation-associated gene 5 (MDA5) is crucial for producing alpha interferon (IFN-α) during Theiler
Area of Science:
- Neuroimmunology
- Virology
- Infectious Diseases
Background:
- Theiler's murine encephalomyelitis virus (TMEV) infection triggers cytokine production via Toll-like receptor and MDA5 pathways.
- The specific role of MDA5 in TMEV-induced cytokine activation and demyelinating disease pathogenesis remains unclear.
Purpose of the Study:
- To investigate the involvement and function of MDA5 in TMEV-induced cytokine gene activation.
- To determine the role of MDA5 in the pathogenesis of TMEV-induced demyelinating disease.
Main Methods:
- Utilized MDA5-deficient 129SvJ mice and wild-type controls.
- Analyzed viral loads, demyelinating lesions, clinical symptoms, and cytokine/chemokine levels in the central nervous system (CNS).
- Examined isolated CNS glial cells for IFN-α production upon viral infection.
Main Results:
- MDA5-deficient mice exhibited higher viral loads and exacerbated demyelinating lesions in the CNS.
- These mice showed reduced IFN-α production but elevated chemokines and cellular infiltration.
- Isolated glial cells from MDA5-deficient mice had impaired IFN-α production, leading to increased viral replication and inflammation.
Conclusions:
- MDA5 is critical for early IFN-α production following TMEV infection.
- Lack of MDA5-mediated IFN-α contributes to increased viral load and CNS inflammation, driving demyelinating disease pathogenesis.
- MDA5 plays a protective role against TMEV-induced demyelinating disease.
