Related Experiment Videos
Prolonged gray matter disease without demyelination caused by Theiler's murine encephalomyelitis virus with a
I Tsunoda1, Y Wada, J E Libbey
1Department of Neurology, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA.
Abstract:
Theiler's murine encephalomyelitis virus (TMEV) is divided into two subgroups based on neurovirulence. During the acute phase, DA virus infects cells in the gray matter of the central nervous system (CNS). Throughout the chronic phase, DA virus infects glial cells in the white matter, causing demyelinating disease. Although GDVII virus also infects neurons in the gray matter, infected mice developed a severe polioencephalomyelitis, and no virus is detected in the white matter or other areas in the CNS in rare survivors. Several sequence differences between the two viruses are located in VP2 puff B and VP1 loop II, which are located near each other, close to the proposed receptor binding site. We constructed a DA virus mutant, DApBL2M, which has the VP1 loop II of GDVII virus and a mutation at position 171 in VP2 puff B. While DApBL2M virus replicated less efficiently than DA virus during the acute phase, DApBL2M-induced acute polioencephalitis was comparable to that in DA virus infection. Interestingly, during the chronic phase, DApBL2M caused prolonged gray matter disease in the brain without white matter involvement in the spinal cord. This is opposite what is observed during wild-type DA virus infection. Our study is the first to demonstrate that conformational differences via interaction of VP2 puff B and VP1 loop II between GDVII and DA viruses can play an important role in making the transition of infection from the gray matter in the brain to the spinal cord white matter during TMEV infection.
Insights
Theiler's murine encephalomyelitis virus (TMEV) subgroups differ in neurovirulence. VP2 puff B and VP1 loop II interactions influence TMEV
Area of Science:
- Neurovirology
- Molecular Virology
- Central Nervous System (CNS) Pathogenesis
Background:
- Theiler's murine encephalomyelitis virus (TMEV) exhibits distinct neurovirulence patterns between subgroups.
- DA virus causes acute gray matter and chronic white matter CNS disease, while GDVII virus induces severe polioencephalomyelitis.
- Sequence differences in VP2 puff B and VP1 loop II near the receptor binding site are implicated in TMEV neurovirulence.
Purpose of the Study:
- To investigate the role of VP2 puff B and VP1 loop II interactions in TMEV neurovirulence and CNS disease progression.
- To determine how specific viral protein structures influence the transition of infection from gray to white matter.
Main Methods:
- Construction of a chimeric TMEV mutant (DApBL2M) with GDVII virus VP1 loop II and a VP2 puff B mutation.
- Comparative analysis of viral replication efficiency and neuropathogenesis between wild-type DA virus and DApBL2M in mice.
- Assessment of acute and chronic phase disease manifestations in the central nervous system.
Main Results:
- DApBL2M replicated less efficiently than DA virus but induced comparable acute polioencephalitis.
- DApBL2M caused prolonged gray matter disease in the brain during the chronic phase, with no white matter involvement in the spinal cord.
- This contrasts with wild-type DA virus, which progresses to white matter disease.
Conclusions:
- Conformational differences in the interaction between VP2 puff B and VP1 loop II are critical for TMEV pathogenesis.
- These structural variations dictate the virus's ability to transition from gray matter infection in the brain to white matter involvement in the spinal cord.
- This study provides novel insights into the molecular mechanisms underlying TMEV-induced demyelinating disease.