Differential expression of interferon responsive genes in rodent models of transmissible spongiform encephalopathy disease
1 Division of Host Genetics and Prion Diseases, Public Health Agency of Canada, Canadian Science Centre for Human and Animal Health, Winnipeg, MB R3E 3R2, Canada
2 Department of Medical Microbiology and Infectious Diseases, Faculty of Medicine, University of Manitoba, Winnipeg, MB R3E 0W3, Canada
3 Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, MB R3E 0W3, Canada
4 Department of Dermatology and Human Molecular Genetics Center, MCW, Milwaukee, WI 53226, USA
5 Department of Biochemistry, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA
Molecular Neurodegeneration 2007, 2:5 doi:10.1186/1750-1326-2-5Published: 16 March 2007
The pathological hallmarks of transmissible spongiform encephalopathy (TSE) diseases are the deposition of a misfolded form of a host-encoded protein (PrPres), marked astrocytosis, microglial activation and spongiosis. The development of powerful gene based technologies has permitted increased levels of pro-inflammatory cytokines to be demonstrated. However, due to the use of assays of differing sensitivities and typically the analysis of a single model system it remained unclear whether this was a general feature of these diseases or to what extent different model systems and routes of infection influenced the relative levels of expression. Similarly, it was not clear whether the elevated levels of cytokines observed in the brain were accompanied by similar increases in other tissues that accumulate PrPres, such as the spleen.
The level of expression of the three interferon responsive genes, Eif2ak2, 2'5'-OAS, and Mx2, was measured in the brains of Syrian hamsters infected with scrapie 263K, VM mice infected with bovine spongiform encephalopathy and C57BL/6 mice infected with the scrapie strain ME7. Glial fibrillary acidic expression confirmed the occurrence of astrocytosis in all models. When infected intracranially all three models showed a similar pattern of increased expression of the interferon responsive genes at the onset of clinical symptoms. At the terminal stage of the disease the level and pattern of expression of the three genes was mostly unchanged in the mouse models. In contrast, in hamsters infected by either the intracranial or intraperitoneal routes, both the level of expression and the expression of the three genes relative to one another was altered. Increased interferon responsive gene expression was not observed in a transgenic mouse model of Alzheimer's disease or the spleens of C57BL/6 mice infected with ME7. Concurrent increases in TNFα, TNFR1, Fas/ApoI receptor, and caspase 8 expression in ME7 infected C57BL/6 mice were observed.
The identification of increased interferon responsive gene expression in the brains of three rodent models of TSE disease at two different stages of disease progression suggest that this may be a general feature of the disease in rodents. In addition, it was determined that the increased interferon responsive gene expression was confined to the CNS and that the TSE model system and the route of infection influenced the pattern and extent of the increased expression. The concurrent increase in initiators of Eif2ak2 mediated apoptotic pathways in C57BL/6 mice infected with ME7 suggested one mechanism by which increased interferon responsive gene expression may enhance disease progression.