Neurological Diseases and Viral Dynamics in the Brains of Neonatally Borna Disease Virus-Infected Gerbils

Watanabe, Makiko; Lee, Byeong-Jae; Kamitani, Wataru; Kobayashi, Takeshi; Taniyama, Hiroyuki; Tomonaga, Keizō; Ikuta, Kazuyoshi

doi:10.1006/viro.2001.0813

Cited by 36 publications

(22 citation statements)

References 36 publications

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“…In particular, the early and intense CRNP5 antigen expression in neurons in the brain stem, at a time when few if any neurons in that region expressed virus antigen in CRP3-infected rats, clearly suggests changes in neural cell tropism and/or the ability of the CRNP5 variant to spread rapidly within the brain. As the brain stem is responsible for basic vital functions of life, including important respiratory and circulation control, the novel ability of CRNP5 to swiftly infect the brain stem neurons is consistent with the rapidly fatal outcome of CRNP5 infection, as has been suggested for the BDV-infected gerbil model (56).…”

Section: Discussionsupporting

confidence: 64%

Enhanced Neurovirulence of Borna Disease Virus Variants Associated with Nucleotide Changes in the Glycoprotein and L Polymerase Genes

Nishino

Kobasa

Rubin

et al. 2002

J Virol

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Borna disease virus (BDV) infection produces a variety of clinical diseases, from behavioral illnesses to classical fatal encephalitis (i.e., Borna disease [BD]). Since the genomes of most BDV isolates differ by less than 5%, host factors are believed responsible for much of the reported variability in disease expression. The contribution of BDV genomic differences to variation in BD expression is largely unexplored. Here we compared the clinical outcomes of rats infected with one of two related BDV variants, CRP3 or CRNP5. Compared to rats inoculated with CRP3, adult and newborn Lewis rats inoculated with CRNP5 had more severe and rapidly fatal neurological disease, with increased damage to the hippocampal pyramidal neurons and rapid infection of brain stem neurons. To identify possible virus-specific contributions to the observed variability in disease outcome, the genomes of CRP3 and CRNP5 were sequenced. Compared to CRP3, there were four nucleotide changes in the CRNP5 variant, two each in the G protein and in the L polymerase, resulting in four amino acid changes. These results suggest that small numbers of genomic differences between BDV variants in the G protein and/or L polymerase can contribute to the variability in BD outcomes.Borna disease virus (BDV) is a nonsegmented negativestrand RNA virus (6) belonging to the family Bornaviridae (13,46). BDV infection in experimental animals has been used to study the pathogenesis of virus-induced central nervous system damage and as a model for specific human diseases, e.g., autism (37). BDV encodes at least six open reading frames (ORFs) in three transcription units: nucleoprotein p40 (N), p10 (X), phosphoprotein p24 (P), matrix protein gp18 (M), membrane glycoprotein gp94 (G), and an RNA-dependent RNA polymerase p190 (L polymerase) (6, 13, 57). Virus replication and transcription take place in the nucleus, a characteristic of Bornaviridae that is unique in the order Mononegavirales (5,8,12,13,46). BDV naturally infects a wide range of warm-blooded hosts (41). In horses and sheep, BDV causes classical Borna disease (BD), a fatal mononuclear inflammatory encephalomyelitis with severe signs of neurological disease (as reviewed in reference 41). Classical BD is in large part due to immunopathogenic damage to the nervous system by blood-borne inflammatory cells (49). However, responses to BDV infection vary according to differences in host-specific factors, e.g., species, animal strain, or age of the host at the time of infection (2, 24, 33, 48). For example, BDV-infected adult Lewis rats develop a highly immunopathogenic central nervous system disease characterized by acute, often fatal encephalitis with clinical signs of hyperactivity, aggression, and ataxia, followed by a chronic phase with resolving encephalitis and depressed behavior (19,41). In contrast, Lewis rats infected as neonates or as immunosuppressed adults do not develop significant inflammatory infiltrates in the brain and may develop behavioral signs of disease without becoming overtly ill (24,33,4...

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Section: Discussionsupporting

confidence: 64%

Enhanced Neurovirulence of Borna Disease Virus Variants Associated with Nucleotide Changes in the Glycoprotein and L Polymerase Genes

Nishino

Kobasa

Rubin

et al. 2002

J Virol

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“…We have reported changes in the N/P ratio during the different stages of BDV infection (32,33). Intriguingly, in BDV persistently infected cells, P was found to be present in about an eightfold molar excess over N (32).…”

Section: Discussionmentioning

confidence: 95%

A Methionine-Rich Domain Mediates CRM1-Dependent Nuclear Export Activity of Borna Disease Virus Phosphoprotein

Yanai

Kobayashi

Hayashi

et al. 2006

J Virol

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Borna disease virus (BDV) is. This observation suggested a unique strategy of intracellular trafficking of a viral protein that is essential for the formation of a functional BDV ribonucleoprotein (RNP). However, neither the mechanism nor the consequences of the cytoplasmic retention or nuclear export of BDV X-P complex have been elucidated. In this study, we show that BDV P contains a bona fide nuclear export signal (NES) and can actively shuttle between the nucleus and cytoplasm. A transient transfection analysis of cDNA clones that mimic the BDV bicistronic X/P mRNA revealed that the methionine-rich (MetR) domain of P is responsible for the X-dependent cytoplasmic localization of the protein complex. Mutational and functional analysis revealed that the methionine residues within the MetR domain are critical for the activity of the NES of P. Furthermore, leptomycin B or small interfering RNA for inhibition of CRM1 strongly suggested that a CRM1-dependent pathway mediates nuclear export of P. Fluorescence loss in photobleaching analysis confirmed the nucleocytoplasmic shuttling of P. Moreover, we revealed that the nuclear export of P is not involved in the inhibition of the polymerase activity by X in the BDV minireplicon system. Our results may provide a unique strategy for the nucleocytoplasmic transport of viral RNP, which could be critical for the formation of not only infectious virions in the cytoplasm but also a persistent viral state in the nucleus.Riboviruses, whose RNA biosynthetic processes, replication, and transcription take place in the nucleus of the infected cell, need to control the directional transport of their genomes through nuclear pore complexes. Recent studies have revealed that viral proteins play central roles in the regulation of nucleocytoplasmic trafficking of viral nucleic acids (2, 24). For instance, the nucleocapsid (NP) and nonstructural (NS2/NEP) proteins of influenza A virus are required for nuclear import and export, respectively, of the viral ribonucleoprotein (RNP) complex (16-18). Likewise, the Rev protein of human immunodeficiency virus type 1 mediates the nuclear transport of unspliced or single-spliced viral transcripts (21). The nucleocytoplasmic transport of viral components is an active and energy-dependent process mediated by specific nuclear localization and export signals termed NLS and NES, respectively, which are present within cargo molecules (2, 7). The interaction between NLS or NES with nuclear transport receptors known as importin and exportin, respectively, regulates the direction in which cargo molecules are transported (7, 23). The signal-dependent translocation of cargo molecules most likely contributes to the nucleocytoplasmic transport of viral components in infected cells, but the detailed mechanisms by which viruses control the directional transport of their genome-protein complexes remain poorly understood.Borna disease virus (BDV) is an enveloped virus with a nonsegmented, negative-strand RNA genome that has a gene organization characteristic of m...

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“…After a blocking step, the sections were incubated with rabbit anti-P polyclonal antibody (1:1,000; ref. 21), anti-GFAP antibody (Zymed), and͞or antisynaptophysin monoclonal antibody (1:10, Chemicon). For detection of transgene product, primary antibodies were detected with biotinylated goat anti-rabbit IgG and avidin-biotin peroxidase complex (Vector Laboratories) by using diaminobenzidine͞H 2 O 2 .…”

Section: Methodsmentioning

confidence: 99%

Glial expression of Borna disease virus phosphoprotein induces behavioral and neurological abnormalities in transgenic mice

Kamitani

Ono

Yoshino

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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One hypothesis for the etiology of behavioral disorders is that infection by a virus induces neuronal cell dysfunctions resulting in a wide range of behavioral abnormalities. However, a direct linkage between viral infections and neurobehavioral disturbances associated with human psychiatric disorders has not been identified. Here, we show that transgenic mice expressing the phosphoprotein (P) of Borna disease virus (BDV) in glial cells develop behavioral abnormalities, such as enhanced intermale aggressiveness, hyperactivity, and spatial reference memory deficit. We demonstrate that the transgenic brains exhibit a significant reduction in brain-derived neurotrophic factor and serotonin receptor expression, as well as a marked decrease in synaptic density. These results demonstrate that glial expression of BDV P leads to behavioral and neurobiological disturbances resembling those in BDVinfected animals. Furthermore, the lack of reactive astrocytosis and neuronal degeneration in the brains indicates that P can directly induce glial cell dysfunction and also suggests that the transgenic mice may exhibit neuropathological and neurophysiological abnormalities resembling those of psychiatric patients. Our results provide a new insight to explore the relationship between viral infections and neurobehavioral disorders. N eurobehavioral disorder is a complex disease that must arise from the actions of many genes and͞or environmental factors. A number of working hypotheses propose that viral infection, as an environmental factor, contributes to the induction of neuropathological and neurophysiological disturbances, resulting in a wide range of behavioral abnormalities (1-3). Studies using animal models reveal that viruses can induce neurobehavioral disturbances predominantly through an indirect pathway that involves the release of various factors by infiltrating cells or by glial cells (3-5). This process seems to be a common pathway to neuronal injury in a wide variety of neurodegenerative disorders in which glial proliferation typically accompanies. In the case of major psychiatric disorders, however, a spectrum of neurological abnormalities associated with glial cell dysfunction is found in brains without neuronal degeneration (2, 6-8). Despite increased insight into the mechanisms of the neuropathogenesis of different viruses, viral infections or specific antigens that develop neurobehavioral abnormalities associated with psychiatric disorders have not yet been identified.Borna disease virus (BDV) is a highly neurotropic virus that belongs to the Mononegavirales. Natural infection of BDV has now been found in a wide variety of vertebrates, suggesting that the host range of this virus probably includes all warm-blooded animals (9, 10). BDV persistently infects the CNS of many animal species and causes behavioral disturbances, such as anxiety, aggression, hyperactivity, abnormal play behavior, and cognitive deficits, reminiscent of autism, schizophrenia, and mood disorders (11)(12)(13)(14). Thus, studies on this virus...

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Neurological Diseases and Viral Dynamics in the Brains of Neonatally Borna Disease Virus-Infected Gerbils

Cited by 36 publications

References 36 publications

Enhanced Neurovirulence of Borna Disease Virus Variants Associated with Nucleotide Changes in the Glycoprotein and L Polymerase Genes

Enhanced Neurovirulence of Borna Disease Virus Variants Associated with Nucleotide Changes in the Glycoprotein and L Polymerase Genes

A Methionine-Rich Domain Mediates CRM1-Dependent Nuclear Export Activity of Borna Disease Virus Phosphoprotein

Glial expression of Borna disease virus phosphoprotein induces behavioral and neurological abnormalities in transgenic mice

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