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: Lin Li, Reiner Ulrich, Wolfgang Baumgärtner, Ingo Gerhauser
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 12 Pg. 242 (Dec 24 2015) ISSN: 1742-2094 [Electronic] England
• PMID: 26703877 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• G1p2 protein, mouse
• Interferon Type I
• Ubiquitins
• eIF-2 Kinase
• protein kinase R, mouse

Topics

• Animals
• Cardiovirus Infections (immunology)
• Cytokines (immunology)
• Disease Models, Animal
• Disease Resistance (immunology)
• Female
• Fluorescent Antibody Technique
• Immunity, Innate (immunology)
• Immunohistochemistry
• Interferon Type I (immunology)
• Mice
• Mice, Inbred C57BL
• Multiple Sclerosis (immunology)
• Oligonucleotide Array Sequence Analysis
• Reverse Transcriptase Polymerase Chain Reaction
• Spinal Cord (pathology)
• Theilovirus (immunology)
• Ubiquitins (immunology)
• eIF-2 Kinase (immunology)