title: Interferon-stimulated genes-essential antiviral effectors implicated in resistance to Theiler's virus-induced demyelinating disease.
abstract: BACKGROUND
  Experimental infection of mice with Theiler's murine encephalomyelitis virus (TMEV) is used as an animal model of human multiple sclerosis. TMEV persists in susceptible mouse strains and causes a biphasic disease consisting of acute polioencephalomyelitis and chronic demyelinating leukomyelitis. In contrast, resistant mice eliminate the virus within 2 to 4 weeks, which seems to be based on a strong antiviral innate immune response including the activation of the type I interferon (IFN) pathway. Several interferon-stimulated genes (ISGs) such as IFN-stimulated protein of 15 kDa (ISG15), protein kinase R (PKR), and 2'5'-oligoadenylate synthetase (OAS) function as antiviral effectors and might contribute to virus elimination. Nevertheless, detailed investigations of the type I IFN pathway during TMEV-induced demyelinating disease (TMEV-IDD) are lacking.
  
  
  METHODS
  The present study evaluated microarray data of the spinal cord obtained from susceptible SJL/J mice after TMEV infection focusing on IFN-related genes. Moreover, ISG gene and protein expression was determined in mock- and TMEV-infected SJL/J mice and compared to its expression in resistant C57BL/6 mice using real- time PCR, immunohistochemistry, and immunofluorescence.
  
  
  RESULTS
  Interestingly, despite of increased ISG gene expression during TMEV-IDD, ISG protein expression was impaired in SJL/J mice and mainly restricted to demyelinated lesions. In contrast, high ISG protein levels were found in spinal cord gray and white matter of C57BL/6 compared to SJL/J mice in the acute and chronic phase of TMEV-IDD. In both mouse strains, ISG15 was mainly found in astrocytes and endothelial cells, whereas PKR was predominantly expressed by microglia/macrophages, oligodendrocytes, and neurons. Only few cells were immunopositive for OAS proteins.
  
  
  CONCLUSIONS
  High levels of antiviral ISG15 and PKR proteins in the spinal cord of C57BL/6 mice might block virus replication and play an important role in the resistance to TMEV-IDD.
authors.affiliation: Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, 30559, Hannover, Germany. Lin.Li@tiho-hannover.de.|Center of Systems Neuroscience Hannover, Hannover, Germany. Lin.Li@tiho-hannover.de.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, 30559, Hannover, Germany. Reiner.Ulrich@fli.bund.de.|Center of Systems Neuroscience Hannover, Hannover, Germany. Reiner.Ulrich@fli.bund.de.
authors.forename: Reiner
authors.initials: R
authors.lastname: Ulrich
authors.affiliation: Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, 30559, Hannover, Germany. Wolfgang.Baumgaertner@tiho-hannover.de.|Center of Systems Neuroscience Hannover, Hannover, Germany. Wolfgang.Baumgaertner@tiho-hannover.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baumgärtner
authors.affiliation: Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, 30559, Hannover, Germany. Ingo.Gerhauser@tiho-hannover.de.
authors.forename: Ingo
authors.initials: I
authors.lastname: Gerhauser
mesh_terms: D000818:Animals; D018188:Cardiovirus Infections / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D004195:Disease Models, Animal; D060467:Disease Resistance / Q000276:immunology*; D005260:Female; D005455:Fluorescent Antibody Technique; D007113:Immunity, Innate / Q000276:immunology; D007150:Immunohistochemistry; D007370:Interferon Type I / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000473:pathology; D017945:Theilovirus / Q000276:immunology; D014452:Ubiquitins / Q000276:immunology; D019892:eIF-2 Kinase / Q000276:immunology*
chemical_list: D016207:Cytokines; C489550:G1p2 protein, mouse; D007370:Interferon Type I; D014452:Ubiquitins; D019892:eIF-2 Kinase; C000605978:protein kinase R, mouse