Identification and characterization of viral and cellular factors that protect from Bornavirus-induced neuronal degeneration in the hippocampus

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Little is known about host cell factors and cellular signaling pathways that prevent from virus-induced neuronal degeneration in the central nervous system. Using hippocampal slice cultures of various rat strains we could recently show that the Borna disease virus (BDV) induced degeneration of granule cell neurons of the dentate gyrus is dependent on the rat genetic background and prevented by soluble host factors. Our goal is now to identify the protective factors by biochemical methods, including enrichment and subsequent identification by mass spectrometry-based analysis. Functional experiments will be applied to characterize the potency of these factors to protect from neuronal cell death. We also could identify by genome-wide association studies (GWAS) one resistance locus in Sprague-Dawley rats harboring several candidate genes. To gain insight into the cellular signaling events that triggers neuronal survival, we want to investigate the involvement of the cellular candidate genes identified by GWAS by knock-down and overexpression approaches using newly developed BDV vectors encoding functional miRNAs. Finally, we want to challenge our hypothesis that the viral X protein contributes to neuronal survival in infected hippocampal cultures by interfering with cellular apoptosis pathways to promote chronic infection. With these studies we hope to shed light onto the poorly investigated host response pathways that are involved in virus-induced neuronal degeneration.