Borna disease (BD) is a neurologic syndrome characterized by behavioral disturbances and the accumulation of specific proteins in limbic system neurons. A viral etiology has been proposed because BD can be induced in birds, rodents, and primates by inoculation with filtered brain homogenates from animals with BD. We report here the isolation and preliminary characterization of cDNA clones from a rat with BD. These clones hybridized to specific transcripts in BD rat brain and arrested in vitro translation ofBD proteins. In situ hybridization experiments using RNA probes prepared from these clones showed an abundance of these transcripts in limbic system neurons. Northern (RNA) hybridizations using these RNA probes indicated that the BD agent is probably a virus with major transcripts of 8.5, 2.1, and 0.8 kilobases.Borna disease (BD) is an immune-mediated neurologic syndrome characterized by profound abnormalities in behavior. Although BD was initially described as an epidemic disease in horses and other livestock, the disease has been experimentally induced in a wide variety of vertebrates, including birds, rodents, and primates, through inoculation of filtered brain extracts from infected animals (1-6). Because the potency of such extracts to induce disease is reduced by exposure to UV or detergents, the BD agent has been suggested to be an enveloped virus (1, 7).Animals with BD produce antibodies that recognize 60 kDa, 38/40-kDa, 25-kDa, and 14.5-kDa proteins in brains of infected animals and in infected cell cultures (1,3,8,9). These proteins are thought to be encoded by the BD agent because they are present in all animals with BD and because antibodies from one host species recognize the same panel of proteins in other species with BD (1,3,8,9).The behavioral manifestations of BD vary with the host species. Birds and livestock show motor disturbances (1, 3). Rats have a biphasic course. The acute phase is characterized by displays of aggression, hyperactivity, and ataxia; this phase is followed over a period of several weeks by listlessness, blindness, and, in some animals, by paralysis or obesity (4,5). These biphasic abnormalities in rat behavior have been correlated with specific alterations in neurotransmitter mRNA levels (6). Tree shrews show abnormalities in social and sexual behaviors (2). In each of these host species, BD proteins are present primarily in limbic system neurons (1,3,5). Recent studies suggest that the host range for BD may extend to man. Antibodies to BD proteins have been described in patients with bipolar depressive disorders, in intravenous drug abusers, and in individuals seropositive for human immunodeficiency virus (10)(11)(12).Interest in BD as a model for virus-induced behavioral disorders and recognition ofthe potential role of BD in human neuropsychiatric disease led us to attempt characterization of the BD agent. Because classical methods for purification of viral particles had not been successful, we adopted a recombinant DNA approach to study this unusual infectiou...
Borna disease virus is an uncharacterized agent that causes sporadic but fatal neurological disease in horses and sheep in Europe. Studies of the infection in rats have shown that the agent has a strict tropism for neural tissues, in which it persists indefinitely. Inoculated rats developed encephalitis after an incubation period of 17 to 90 days. This report shows that the incubation period is the time required for transport of the agent in dendritic-axonal processes from the site of inoculation to the hippocampus. The immune responses to the agent had no effect on replication or transport of the virus. The neural conduit to the brain was proven by intranasal inoculation of virus that resulted in rapid transport of the agent via olfactory nerves to the hippocampus and in development of disease in 20 days. Virus inoculation into the feet resulted in spread along nerve fibers from neuron to neuron. There was sequential replication in neurons of the dorsal root ganglia adjacent to the lumbar spinal cord, the gracilis nucleus in the medulla, and pyramidal cells in the cerebral cortex, followed by infection of the hippocampal neurons and onset of disease. This progression required 50 to 60 days. The exclusiveness of the neural conduit was proven by failure to cause infection after injection of the virus intravenously or into the feet of neurectomized rats.
Knowledge of bornaviruses has expanded considerably during the last decade. A possible reservoir of mammalian Borna disease virus has been identified, divergent bornaviruses have been detected in birds and reptiles, and endogenous bornavirus-like elements have been discovered in the genomes of vertebrates of several species. Previous sequence comparisons and alignments have indicated that the members of the current family Bornaviridae are phylogenetically diverse and are not adequately classified in the existing bornavirus taxonomy supported by the International Committee on Taxonomy of Viruses (ICTV). We provide an update of these analyses and describe their implications for taxonomy. We propose retaining the family name Bornaviridae and the genus Bornavirus but reorganizing species classification. PAirwise Sequence Comparison (PASC) of bornavirus genomes and Basic Local Alignment Search Tool (BLAST) comparison of genomic and protein sequences, in combination with other already published phylogenetic analyses and known biological characteristics of bornaviruses, indicate that this genus should include at least five species: Mammalian 1 bornavirus (classical Borna disease virus and divergent Borna disease virus isolate No/98), Psittaciform 1 bornavirus (avian/psittacine bornaviruses 1, 2, 3, 4, 7), Passeriform 1 bornavirus (avian/canary bornaviruses C1, C2, C3, LS), Passeriform 2 bornavirus (estrildid finch bornavirus EF), and Waterbird 1 bornavirus (avian bornavirus 062CG). This classification is also in line with biological characteristics of these viruses and their vertebrate hosts. A snake bornavirus, proposed to be named Loveridge’s garter snake virus 1, should be classified as a member of an additional species (Elapid 1 bornavirus), unassigned to a genus, in the family Bornaviridae. Avian bornaviruses 5, 6, MALL, and another “reptile bornavirus” (“Gaboon viper virus”) should stay unclassified until further information becomes available. Finally, we propose new virus names and abbreviations when necessary to achieve clear differentiation and unique identification.
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