Interferon-stimulated genes-essential antiviral effectors implicated in resistance to Theiler's virus-induced
Lin Li1,2, Reiner Ulrich3,4, Wolfgang Baumgärtner5,6
1Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, 30559, Hannover, Germany. Lin.Li@tiho-hannover.de.
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.
Insights
Resistant mice show high interferon-stimulated gene (ISG) protein levels, like ISG15 and PKR, crucial for controlling Theiler's murine encephalomyelitis virus (TMEV) infection and preventing demyelinating disease.
Area of Science:
- Neuroimmunology
- Virology
- Infectious Diseases
Background:
- Theiler's murine encephalomyelitis virus (TMEV) infection in mice models human multiple sclerosis.
- TMEV causes biphasic disease (acute polioencephalomyelitis and chronic demyelinating leukomyelitis) in susceptible strains.
- Resistant mice clear TMEV via innate immunity, including type I interferon (IFN) pathway activation.
Purpose of the Study:
- Investigate the role of the type I interferon (IFN) pathway in TMEV-induced demyelinating disease (TMEV-IDD).
- Analyze gene and protein expression of key interferon-stimulated genes (ISGs) like ISG15, PKR, and OAS in susceptible and resistant mice.
Main Methods:
- Microarray analysis of spinal cord tissue from TMEV-infected SJL/J mice.
- Real-time PCR, immunohistochemistry, and immunofluorescence to assess ISG expression in SJL/J and C57BL/6 mice.
- Comparison of ISG protein levels in mock- and TMEV-infected mice during acute and chronic phases.
Main Results:
- Despite increased ISG gene expression in susceptible SJL/J mice, protein expression was impaired and localized to lesions.
- Resistant C57BL/6 mice exhibited high ISG protein levels (ISG15, PKR) in spinal cord gray and white matter.
- ISG15 localized to astrocytes and endothelial cells; PKR was found in microglia/macrophages, oligodendrocytes, and neurons.
Conclusions:
- High ISG15 and PKR protein levels in resistant mice likely inhibit TMEV replication.
- These antiviral proteins may be critical for resistance to TMEV-induced demyelinating disease.
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