Interferon-stimulated genes-essential antiviral effectors implicated in resistance to Theiler's virus-induced demyelinating disease

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.