The L-coding region of the DA strain of Theiler's murine encephalomyelitis virus causes dysfunction and death of myelin-synthesizing cells

J Virol. 2011 Sep;85(18):9377-84. doi: 10.1128/JVI.00178-11. Epub 2011 Jul 13.

Abstract

The DA strain and other members of the TO subgroup of Theiler's murine encephalomyelitis virus (TMEV) induce an early transient subclinical neuronal disease followed by a chronic progressive inflammatory demyelination, with persistence of the virus in the central nervous system (CNS) for the life of the mouse. Although TMEV-induced demyelinating disease (TMEV-IDD) is thought to be immune mediated, there is also evidence that supports a role for the virus in directly inducing demyelination. In order to clarify the function of DA virus genes, we generated a transgenic mouse that had tamoxifen-inducible expression of the DA L-coding region in oligodendrocytes (and Schwann cells), a cell type in which the virus is known to persist. Tamoxifen-treated young transgenic mice usually developed an acute progressive fatal paralysis, with abnormalities of the oligodendrocytes and Schwann cells and demyelination, but without significant lymphocytic infiltration; later treatment led to transient weakness with demyelination and persistent expression of the recombined transgene. These findings demonstrate that a high level of expression of DA L can cause the death of myelin-synthesizing cells and death of the mouse, while a lower level of L expression (which can persist) can lead to cellular dysfunction with survival. The results suggest that expression of DA L plays an important role in the pathogenesis of TMEV-IDD. Virus-induced infection and death of oligodendrocytes may play a part in the demyelination of other diseases in which an immune-mediated mechanism has been stressed, including multiple sclerosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Death*
  • Demyelinating Diseases
  • Disease Models, Animal
  • Mice
  • Mice, Transgenic
  • Neurons / metabolism
  • Neurons / pathology*
  • Neurons / virology*
  • Oligodendroglia / pathology
  • Oligodendroglia / virology
  • Poliomyelitis / pathology
  • Poliomyelitis / virology
  • RNA, Viral / genetics*
  • Rodent Diseases / pathology
  • Rodent Diseases / virology
  • Schwann Cells / pathology
  • Schwann Cells / virology
  • Theilovirus / pathogenicity*
  • Viral Proteins / metabolism*
  • Virulence Factors / metabolism*

Substances

  • RNA, Viral
  • Viral Proteins
  • Virulence Factors