Borna disease virus (BDV) is a neurotropic nonsegmented negative-stranded RNA virus that persistently infects warm-blooded animals. In horses and other natural animal hosts, infections with BDV cause meningoencephalitis and behavioral disturbances. Experimental infection of adult mice takes a nonsymptomatic course, an observation previously believed to indicate that this animal species is not suitable for pathogenesis studies. We now demonstrate that BDV frequently induces severe neurological disease in infected newborn mice. Signs of neurological disease were first observed 4 to 6 weeks after intracerebral infection. They included a characteristic nonphysiological position of the hind limbs at an early stage of the disease and paraparesis at a later stage. Histological examination revealed large numbers of perivascular and meningeal inflammatory cells in brains of diseased mice and, unexpectedly, no increase in immunoreactivity to glial fibrillar acidic protein. The incidence and severity of BDV-induced disease varied dramatically among mouse strains. While only 13% of the infected C57BL/6 mice showed disease symptoms, which were mostly transient, more than 80% of the infected MRL mice developed severe neurological disorder. In spite of these differences in susceptibility to disease, BDV replicated to comparable levels in the brains of mice of the various strains used. Intracerebral infections of newborn β2-microglobulin-deficient C57BL/6 and MRL mice, which both lack CD8+ T cells, did not result in meningoencephalitis or neurological disease, indicating that the BDV-induced neurological disorder in mice is a cytotoxic T-cell-mediated immunopathological process. With this new animal model it should now be possible to characterize the disease-inducing immune response to BDV in more detail.
Borna disease virus (BDV) causes CD8؉ T-cell-mediated meningoencephalitis in immunocompetent mice and rats, thus providing a valuable animal model for studying the mechanisms of virus-induced central nervous system (CNS) immunopathology. Chemokine-mediated leukocyte recruitment to the CNS is a crucial step in the development of neurological disease. We found increased mRNA levels of IP-10 and other chemokines in brains of adult rats following infection with BDV. The marked increase in chemokine gene expression at about day 8 postinfection seemed to immediately precede the inflammatory process. In brains of rats infected as newborns, in which inflammation was only mild and transient, sustained expression of IP-10 and RANTES genes was observed. In situ hybridization studies revealed that astrocytes were the major source of IP-10 mRNAs in brains of rats infected as newborns and as adults. In brains of infected mice lacking CD8 ؉ T cells (2m 0/0 ), transcripts encoding IP-10 and RANTES were also observed. IP-10 transcripts were also present in a small number of scattered astrocytes of infected knockout mice lacking mature B and T cells as well as functional alpha/beta and gamma interferon receptors, indicating that BDV can induce chemokine synthesis in the absence of interferons and other B-or T-cell-derived cytokines. These data provide strong evidence that CNS-resident cells are involved in the early localized host immune response to infection with BDV and support the concept that chemokines are pivotal for the initiation of virus-induced CNS inflammation.
It has previously been reported that de novo infection of primary rabbit brain cells with Borna disease virus (BDV) can be blocked with interferon-alpha/beta (IFN), whereas this cytokine has no inhibitory effect on BDV in persistently infected rat lung cells [v. Rheinbaben et al., J. Gen. Virol. (1985) 66: 2,777-2,780]. It remained unclear, however, whether these results indicated that IFN exclusively targets early steps of the BDV replication cycle or whether they simply reflected cell line differences. We now show that BDV replication was effectively inhibited by IFN in both acutely and persistently infected monkey Vero cells. By contrast, IFN had no clear protective effect on either de novo or persistent BDV infections of rat C6 glioblastoma cells. IFN protected C6 cells from the cytopathic effects of vesicular stomatitis virus, excluding the possibility that these cells are devoid of a functional IFN system. In primary rat fibroblasts and in a human oligodendroglial cell line, IFN induced an efficient antiviral state against BDV. These results indicate that BDV is highly susceptible to the antiviral effect of IFN in some cell lines, while others seem to lack undefined components of the IFN system which mediate protection against BDV.
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