SummaryNuclear factor kappa B (NF-kB) is a key regulator of the immune response, but in almost the same manner it is involved in induction of inflammation, proliferation and regulation of apoptosis. In the central nervous system activated NF-kB plays a neuroprotective role. While in some neurodegenerative disorders the role of NF-kB is well characterized, there is poor knowledge on the role of NF-kB in prion disease. We found binding but no transcriptional activity of the transcription factor in vitro. Characterizing the mechanism of cell death after infection with pathological prion protein increased caspase-9 and caspase-3 activity was detected and the lack of NF-kB activity resulted in the inability to activate target genes that usually play an important role in neuroprotection. Additionally, we investigated the role of NF-kB after prion infection of Nfkb1 Nfkb2-/-and Bcl3 -/-mice and central nervous system-specific p65-deleted mice revealing an accelerated prion disease in NF-kB2-and Bcl-3-deficient mice, which is in line with a reduced neuroprotective activity in prion infection. Based on our findings, we propose a model whereby the alteration of NF-kB activity at the early stages of infection with pathological prion protein leads to neuronal cell death mediated by mitochondrial apoptosis.

Transition from G 2 to M phase, a cell cycle checkpoint, is regulated by the Cdc2-cyclin B1 complex. Here, we report that persistent infection with Borna disease virus (BDV), a noncytolytic RNA virus infecting the central nervous system, results in decelerated proliferation of infected host cells due to a delayed G 2 -to-M transition. Persistent BDV-infected rat fibroblast cells showed reduced proliferation compared to uninfected cells. In pull-down assays we observed an interaction of the viral nucleoprotein with the Cdc2-cyclin B1 complex. Transfection of the viral nucleoprotein but not of the phosphoprotein also results in decelerated proliferation. This phenomenon was found in BDV-susceptible primary rat fibroblast cells and also in primary mouse cells, which are not susceptible to BDV infection. This is the first evidence that the noncytolytic Borna disease virus can manipulate host cell functions via interaction of the viral nucleoprotein with mitotic entry regulators. BDV preferentially infects and persists in nondividing neurons. The present report could give an explanation for this selective choice of host cell by BDV.Cell division of eukaryotic cells is a highly regulated process. One round of cell division requires accurate duplication of DNA during S phase of the cell cycle and proper segregation of duplicated chromosomes during mitosis. Progression through the cell cycle is mediated by the activation of members of a highly conserved family of protein kinases, the cyclindependent kinases (termed CdkЈs or CdcЈs) (22). Activation of a Cdk requires binding to a specific regulatory subunit, termed a cyclin. These Cdk-cyclin complexes function as universal cell cycle regulators, each controlling a specific transition to the next phase in the cell cycle.The initiation of mitosis in vertebrate cells is triggered by the cyclin-dependent protein kinase Cdk1, also known as Cdc2. The activation of Cdc2 begins with the binding of cyclin B1, whose level gradually increases during S and G 2 phases. The Cdc2-cyclin B1 complex remains in an inactive state before mitosis by phosphorylation of Cdc2 at Thr14 and Tyr15. At the end of G 2 , these residues are dephosphorylated by the phosphatase Cdc25C, and the active Cdc2-cyclin B1 complex is then competent to initiate the events of mitosis (19,20,30).It is well known that many DNA viruses interact with the cell cycle machinery, since they are dependent on the DNA synthesis enzymes for viral replication (reviewed in reference 16). In contrast, little is known about the interference of RNA viruses with cell cycle checkpoints, where our knowledge is almost exclusively based on investigations of human immunodeficiency virus (reviewed in reference 5). In addition, it was recently reported that reovirus, a cytolytic, nonenveloped, double-stranded RNA virus, inhibits cellular proliferation by inducing G 2 cell cycle arrest (25).Borna disease virus (BDV), a noncytolytic single-stranded RNA virus, is the only known member of the Bornaviridae, in the order Mononegavirales. BDV is...

The inducible transcription factor NF-B is commonly activated upon RNA virus infection and is a key

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