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A protein critical for a Theiler's virus-induced immune system-mediated demyelinating disease has a cell
G D Ghadge1, L Ma, S Sato
1Department of Neurology, The University of Chicago, Chicago, Illinois 60637, USA.
Abstract:
TO subgroup strains of Theiler's murine encephalomyelitis virus (TMEV) induce a persistent central nervous system infection and demyelinating disease in mice. This disease serves as an experimental model of multiple sclerosis (MS) because the two diseases have similar inflammatory white matter pathologies and because the immune system appears to mediate demyelination in both processes. We previously reported (H. H. Chen, W. P. Wong, L. Zhang, P. L. Ward, and R. P. Roos, Nat. Med. 1:927-931, 1995) that TO subgroup strains use an alternative initiation codon (in addition to the AUG used to synthesize the picornavirus polyprotein from one long open reading frame) to translate L*, a novel protein that is out of frame with the polyprotein and which plays a key role in the demyelinating disease. We now demonstrate that L* has antiapoptotic activity in macrophage cells and is critical for virus persistence. The antiapoptotic action of L* as well as the differential translation of L* and virion capsid proteins may foster virus persistence in macrophages and interfere with virus clearance. The regulation of apoptotic activity in inflammatory cells may be important in the pathogenesis of TMEV-induced demyelinating disease as well as MS.
Insights
Theiler
Area of Science:
- Virology
- Neuroimmunology
- Molecular Biology
Background:
- Theiler's murine encephalomyelitis virus (TMEV) TO subgroup causes persistent central nervous system infections in mice.
- This TMEV model mimics aspects of multiple sclerosis (MS) pathology, including white matter inflammation and immune-mediated demyelination.
- Previous work identified the non-structural protein L* as crucial for TMEV-induced demyelinating disease.
Purpose of the Study:
- To investigate the function of the TMEV-encoded L* protein.
- To determine the role of L* in viral persistence and pathogenesis.
- To explore the impact of L* on macrophage apoptosis.
Main Methods:
- Macrophage cell culture and infection with TMEV.
- Analysis of L* protein expression and function.
- Assessment of apoptosis in infected cells.
- Studies on viral persistence and clearance mechanisms.
Main Results:
- The L* protein exhibits antiapoptotic activity in macrophage cells.
- L* is critical for the persistence of TMEV infection.
- Differential translation of L* and capsid proteins may contribute to macrophage persistence and impaired viral clearance.
Conclusions:
- The antiapoptotic function of L* is a key factor in TMEV persistence.
- Regulation of apoptosis in inflammatory cells, potentially mediated by viral proteins like L*, is important in TMEV demyelinating disease.
- Understanding L*'s role may offer insights into the pathogenesis of MS.