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(a) Hydrocephalus ex vacuo in a heterozygous (rnu/+) Rowett rat 100 days after infection (haematoxylin and eosin, x 10). (b) Chronic retinitis with progressive loss of the photoreceptors and nuclear layers in a heterozygous (rnu/+ ) Rowett rat 100 days after infection; 1, remnants of the retina; 2, sclera (haematoxylin and eosin, x 300). 

(a) Hydrocephalus ex vacuo in a heterozygous (rnu/+) Rowett rat 100 days after infection (haematoxylin and eosin, x 10). (b) Chronic retinitis with progressive loss of the photoreceptors and nuclear layers in a heterozygous (rnu/+ ) Rowett rat 100 days after infection; 1, remnants of the retina; 2, sclera (haematoxylin and eosin, x 300). 

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Homozygous athymic nude rats (rnu/rnu) infected intracerebrally with Borna disease virus produced relatively high titres of infectious virus in the central nervous system. However, no clinical signs of disease or pathological alterations could be found during a 100 day observation period. In contrast, heterozygous euthymic albino littermates (rnu/+...

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... when heterozygous euthymic albino littermates ( r n u / + ) were used for infection, the disease followed its regular course irrespective of age (1 or 5 months) of the animals. Like Lewis rats, these animals developed encephalitis and retinitis (Fig. 2) which led to hydrocephalus (Fig. 3) and loss of cells of the nuclear layers. The neurological symptoms, as evidenced by changes in behaviour and blindness, corresponded to those described for Lewis rats. The heterozygous rats produced infectious virus in the CNS and virus-specific serum antibodies (Fig. 2, Tables 1 and 2). Despite high antibody titres, the sera did not neutralize the infectivity of BD virus. These findings show that the heterozygous (rnu/+) Rowett rat is comparable to the Lewis rat with respect to its susceptibility to BD virus infection, and therefore represents a suitable control for the experiments with their nude ...

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... Borna Disease in MammalsBornaviruses are known to establish non-cytolytic infections of their target cells, and direct damage is thus assumed to be limited[164,165]. Instead, BoDV-1-induced disease in non-reservoir hosts was shown to result from immunopathology mediated by virus-specific T lymphocytes[162].The first evidence of an immunopathogenesis was achieved by observations that immunodeficiency in rats due to athymy, thymectomy or immunosuppressive treatment with cyclophosphamide, cyclosporine A (CsA) or corticosteroids resulted in dampened or even completely absent clinical disease and inflammatory infiltrates despite persistent BoDV-1 infection[139,[166][167][168][169][170][171]. Adoptive transfer of splenocytes or brain lymphocytes derived from diseased immunocompetent BoDV-1-infected rats rapidly induced disease in infected immunocompromised healthy animals[166,169,[171][172][173][174][175]. ...
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Avian bornaviruses constitute a genetically diverse group of at least 15 viruses belonging to the genus Orthobornavirus within the family Bornaviridae. After the discovery of the first avian bornaviruses in diseased psittacines in 2008, further viruses have been detected in passerines and aquatic birds. Parrot bornaviruses (PaBVs) possess the highest veterinary relevance amongst the avian bornaviruses as the causative agents of proventricular dilatation disease (PDD). PDD is a chronic and often fatal disease that may engulf a broad range of clinical presentations, typically including neurologic signs as well as impaired gastrointestinal motility, leading to proventricular dilatation. It occurs worldwide in captive psittacine populations and threatens private bird collections, zoological gardens and rehabilitation projects of endangered species. In contrast, only little is known about the pathogenic roles of passerine and waterbird bornaviruses. This comprehensive review summarizes the current knowledge on avian bornavirus infections, including their taxonomy, pathogenesis of associated diseases, epidemiology, diagnostic strategies and recent developments on prophylactic and therapeutic countermeasures.
... We found that neutralizing antibodies were present at very low level or absent in the animals at 12 weeks after administration. In wild-type BoDV infection, presence of neutralizing antibodies in infected animals has been controversial 23,[26][27][28][29] . Neutralizing antibodies could be produced long time after infection 28,29 , which are directed against viral G and M proteins [29][30][31] . ...
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RNA virus-based episomal vector (REVec) is an emerging viral vector system that mediates long-term stable gene expression in variety of cell types in vitro. However, little is known about its tissue tropism and persistence of gene expression in vivo. Here, to evaluate the feasibility of REVec for in vivo gene delivery, we conducted biodistribution analysis of transmission competent REVec and transmission defective ΔG-REVec in Lewis rats. Following intracranial administration of REVec, transgene expression was detected in various tissues. In contrast, transgene expression was only observed in the brain after ΔG-REVec administration. Low levels of vector shedding in the feces and blood and of neutralizing antibody in the serum were detected after REVec injection. In the brain, microglia, astrocytes and neurons were susceptible to REVec-mediated transduction. However, the animals administered with REVec, but not with ΔG-REVec showed a significant decrease in body weight compared to mock treated animals. Additionally, CD8 T cell infiltration was observed in the brain of these animals. In summary, we demonstrated that REVec promotes long-term transgene expression in vivo without causing high vector shedding or neutralizing antibody production; however, suggests the need to attenuate vector associated pathogenicity in the future.
... There is no commercially available vaccine for any mammalian or avian bornaviruses and only experimental data or older date from vaccination in eastern Germany exists. Due to the viral persistence with simultaneous presence of high levels of virus-specific antibodies, humoral immunity obviously does not play a major role, either for mammalian or avian bornaviruses (Narayan et al., 1983a;Herzog et al., 1985;Stitz et al., 1989;Heffels-Redmann et al., 2011;Heffels-Redmann et al., 2012;Piepenbring et al., 2012;Herden et al., 2013;Rubbenstroth et al., 2013;Rubbenstroth et al., 2014a;Piepenbring et al., 2016). ...
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Borna disease has been assessed according to the criteria of the Animal Health Law (AHL), in particular criteria of Article 7 on disease profile and impacts, Article 5 on the eligibility of Borna disease to be listed, Article 9 for the categorisation of Borna disease according to disease prevention and control rules as in Annex IV and Article 8 on the list of animal species related to Borna disease. The assessment has been performed following a methodology composed of information collection and compilation, expert judgement on each criterion at individual and, if no consensus was reached before, also at collective level. The output is composed of the categorical answer, and for the questions where no consensus was reached, the different supporting views are reported. Details on the methodology used for this assessment are explained in a separate opinion. According to the assessment performed, Borna disease cannot be considered eligible to be listed for Union intervention as laid down in Article 5(3) of the AHL because there was no compliance on criterion 5 A(v). Consequently, the assessment on compliance of Borna disease with the criteria as in Annex IV of the AHL, for the application of the disease prevention and control rules referred to in Article 9(1) is not applicable, as well as which animal species can be considered to be listed for Borna disease according to Article 8(3) of the AHL.
... These monoclonal antibodies worked best if given before or shortly after infection and they did not prevent encephalitis or disease when given more than 4 days after infection . BoDV-1 infection will not result in disease in athymic nude rats (Herzog et al., 1985 ). Thus the lesions of bornaviral encephalitis in rats are mediated primarily by N-protein-specific CD8+ T cells. ...
Article
Natural bornavirus infections and their resulting diseases are largely restricted to horses and sheep in Central Europe. The disease also occurs naturally in cats, and can be induced experimentally in laboratory rodents and numerous other mammals. Borna disease virus-1 (BoDV-1), the cause of most cases of mammalian Borna disease, is a negative-stranded RNA virus that replicates within the nucleus of target cells. It causes severe, often lethal, encephalitis in susceptible species. Recent events, especially the discovery of numerous new species of bornaviruses in birds and a report of an acute, lethal bornaviral encephalitis in humans, apparently acquired from squirrels, have revived interest in this remarkable family of viruses. The clinical manifestations of the bornaviral diseases are highly variable. Thus, in addition to acute lethal encephalitis, they can cause persistent neurologic disease associated with diverse behavioral changes. They also cause a severe retinitis resulting in blindness. In this review, we discuss both the pathological lesions observed in mammalian bornaviral disease and the complex pathogenesis of the neurologic disease. Thus infected neurons may be destroyed by T-cell-mediated cytotoxicity. They may die as a result of excessive inflammatory cytokine release from microglia. They may also die as a result of a ‘glutaminergic storm’ due to a failure of infected astrocytes to regulate brain glutamate levels.
... Nevertheless, the immune response to a virus can be more pathogenic than the virus infection itself. For example, the often lethal acute CNS inflammatory response that occurs in normal rats infected with the neurotrophic Borna disease virus does not develop in immunocompromised rats, which survive despite persistent infection (5)(6)(7). Even where virus is cleared from the CNS without overt signs of pathology, either the virus infection or the antiviral immune response may have caused immune recognition of normally sequestered CNS Ags. ...
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The loss of blood-brain barrier (BBB) integrity in CNS inflammatory responses triggered by infection and autoimmunity has generally been associated with the development of neurological signs. In the present study, we demonstrate that the clearance of the attenuated rabies virus CVS-F3 from the CNS is an exception; increased BBB permeability and CNS inflammation occurs in the absence of neurological sequelae. We speculate that regionalization of the CNS inflammatory response contributes to its lack of pathogenicity. Despite virus replication and the expression of several chemokines and IL-6 in both regions being similar, the up-regulation of MIP-1beta, TNF-alpha, IFN-gamma, and ICAM-1 and the loss of BBB integrity was more extensive in the cerebellum than in the cerebral cortex. The accumulation of CD4- and CD19-positive cells was higher in the cerebellum than the cerebral cortex. Elevated CD19 levels were paralleled by kappa-L chain expression levels. The timing of BBB permeability changes, kappa-L chain expression in CNS tissues, and Ab production in the periphery suggest that the in situ production of virus-neutralizing Ab may be more important in virus clearance than the infiltration of circulating Ab. The data indicate that, with the possible exception of CD8 T cells, the effectors of rabies virus clearance are more commonly targeted to the cerebellum. This is likely the result of differences in the capacity of the tissues of the cerebellum and cerebral cortex to mediate the events required for BBB permeability changes and cell invasion during virus infection.
... In naturally infected animals and experimentally infected adult rats, neurological disease and behavioral abnormalities appear to be immunopathologic in nature (reviewed in reference 42). Intracerebral infection of athymic or experimentally immunosuppressed adult rats does not produce BD (19,43). In contrast, infection of immunocompetent adult rats results in encephalomyelitis, characterized by perivascular and parenchymal infiltrations of CD4 ϩ and CD8 ϩ T cells whose appearance is correlated with the onset of disease symptoms (33,41). ...
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Borna disease virus (BDV) infection of Lewis rats is the most studied animal model of Borna disease, an often fatal encephalomyelitis. In this experimental model, BDV-specific CD8+ cytotoxic T lymphocytes (CTLs) play a prominent role in the immunopathogenesis of infection by the noncytolytic, persistent BDV. Of the six open reading frames of BDV, CTLs to BDV X (p10) and the l-polymerase have never been studied. In this study, we used plasmid immunization to investigate the CTL response to BDV X and N. Plasmid-based immunization was a potent CTL inducer in Lewis rats. Anti-X CTLs were primed by a single injection of the p10 cDNA. Two codominant p10 epitopes, M1SSDLRLTLL10 and T8LLELVRRL16, associated with the RT1.Al major histocompatibility complex class I molecules of the Lewis rats, were identified. In addition, immunization with a BDV p40-expressing plasmid confirmed the previously reported RT1.Al-restricted A230SYAQMTTY238 peptide as the CTL target for BDV N. In contrast to the CTL responses, plasmid vaccination was a poor inducer of an antibody response to p10. Three injections of a recombinant eukaryotic expression plasmid of BDV p10 were needed to generate a weak anti-p10 immunoglobulin M response. However, the antibody response could be optimized by a protein boost after priming with cDNA.
... konnte anhand von adult-infizierten, athymischen oder immunsuprimierten Ratten gezeigt werden. Diese Tiere konnten zwar persistent mit BDV-infiziert werden, zeigten jedoch weder Krankheitssymptome noch infiltrierende Lymphozyten im Gehirn (Herzog et al., 1985; Stitz et al., 1989). Auf immunhistochemischen Schnitten von Gehirnen erkrankter ...
Article
Enth. ausserdem 1 Sonderabdr. aus: Biological psychiatry ; Bd. 51. 2002. - Beitr. teilw. dt., teilw. engl. Freiburg (Breisgau), Univ., Diss., 2004 (Nicht für den Austausch).
... Hippocampal changes in neonatally and adult infected animals included distinct loss of granule cells in dentate gyrus. Previous investigators reported an absence of cellular inflammatory response to BDV following neonatal infection [Narayan et al., 1983;Herzog et al., 1985;Stitz et al., 1989;Carbone et al., 1991;Sierra-Honigmann et al., 1993;Bautista et al., 1994;Gosztonyi and Ludwig, 1995;Plata-Salamán et al., 1999;Rott and Becht, 1995;Rubin et al., 1999a], a phenomenon ascribed to the immaturity of the rat immune system in the postnatal period. Humoral immune responses to BDV in neonatally-infected animals are also reported to be restricted, with anti-BDV antibody titers remaining below 1:10 through 133 days postinfection. ...
Article
Both genetic and environmental factors contribute to the pathogenesis of a wide variety of neurodevelopmental disorders, including autism, mental retardation, and schizophrenia. Some heritable disorders approach 100% penetrance; nonetheless, even in these disorders, subtle aspects of clinical disease expression may be influenced by the environment. In other disorders with genetic influences, exogenous factors, and the timepoint(s) during nervous system development at which they are introduced, modulate expression of disease. Elucidation of the mechanisms guiding this intricate interplay between host response genes, environmental agents, and the neurodevelopmental context within which these interactions occur, is necessary to understand the continuum of clinical outcomes. This chapter will review the evidence that infectious and immune factors may contribute to the pathogenesis of neurodevelopmental disorders, describe an animal model of neurodevelopmental disorders based upon viral infection, identify processes by which neural circuitry may be compromised, and outline areas for future research.
... Hippocampal changes in neonatally and adult infected animals included distinct loss of granule cells in dentate gyrus. Previous investigators reported an absence of cellular inflammatory response to BDV following neonatal infection (Bautista et al., 1995;Bautista et al., 1994;Carbone et al., 1991;Gosztonyi and Ludwig, 1995;Herzog et al., 1985;Narayan et al., 1983b;Plata-Salam~n et al., 1999;Rott and Becht, 1995;Rubin et al., 1999b;Sierra-Honigmann et al., 1993;Stitz et al., 1989), a phenomenon ascribed to the immaturity of the rat immune system in the postnatal period. Humoral immune responses to BDV in neonatally infected animals are also reported to be restricted, with anti-BDV antibody titers remaining below 1:10 through 133 days postinfection (Carbone et al., 1991). ...
Article
Animal models provide unique opportunities to explore interactions between host and environment. Two models have been established based on Bornavirus infection that provide new insights into mechanisms by which neurotropic agents and/or immune factors may impact developing or mature CNS circuitry to effect complex disturbances in movement and behavior. Distinct losses in DA pathways in the adult infection model, and the associated dramatic movement disorder that accompanies it, make it an intriguing model for tardive dyskinesia and dystonic syndromes. The neuropathologic, physiologic, and neurobehavioral features of BDV infection of neonates indicate that it not only provides a useful model for exploring the mechanisms by which viral and immune factors may damage developing neurocircuitry, but also has significant links to the range of biologic, neurostructural, locomotor, cognitive, and social deficits observed in serious neuropsychiatric illnesses such as autism.
... Rats have been an excellent rodent model for BDV infection, because their immune-mediated disease closely resembles that of naturally infected horses and sheep [35,36,43]. Although light and electron microscopical studies have allowed first insights in BDV-induced neuronal degeneration in the retina [11,20,35], there is still a remarkable lack of knowledge with regard to structural interactions between dying retinal neurons and microglial cells. The latter cells are considered to constitute the functional basis of the brain's response to a wide variety of neuropathologies [14,24,32,35]. ...
... The latter cells are considered to constitute the functional basis of the brain's response to a wide variety of neuropathologies [14,24,32,35]. BDV retinitis has been shown to be accompanied by a dramatic loss of neurons, finally leaving only some retinal ganglion cells (RGCs) intact [20,35]. Therefore, microglial phagocytosis, generally accompanying neuronal cell death [9,10,30,50] should be of functional importance for this virus-induced ocular disorder. ...
... This immuno-and cytochemical study was designed to investigate structural interactions between reactive glia cells and degenerating neurons in a rodent model of BDV-induced retinitis previously described by conventional histology and electron microscopy [11,20,35]. The well characterized pathogenesis, experimentally induced by intracerebral BDV infection of adult Lewis rats and disseminating via retrograde intra-axonal transport of the virus along the optiv nerve to the retina [6,25,33], has also been described following BDV infection of rabbits and monkeys [12,25,26,35,47]. ...
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Neuron-glia interactions in the Borna disease virus (BDV)-infected rat retina were investigated with emphasis on the ultrastructural characterization of degenerative alterations in the ganglion cell and photoreceptor layer. Immuno- and cytochemical techniques were applied to label microglia, macrophages and Müller (macroglial) cells. Four weeks after intracerebral infection of adult rats, the total thickness of the retina was considerably diminished, primarily due to the loss of photoreceptor segments and ganglion cells. A gradual reduction of both plexiform layers was also observed. There was a remarkable increase in the number of microglial cells, predominantly in the ganglion cell and the inner plexiform layers. Ultrastructural analysis confirmed that microglia, but also macrophages, were involved in phagocytosis accompanying severe neuronal degeneration in the ganglion cell and the photoreceptor layer. In contrast, Müller cells showed moderate morphological and cytochemical alterations, indicating that Müller cells play only a minor role in early stages of BDV-induced retinitis. Monitoring neuron-glia interactions in BDV-induced retinopathy, combined with the application of different protocols of immunosuppression effecting the BDV virus and/or the microglia, might help to establish specific strategies to suppress BDV-induced neuronal degeneration.