Borna disease virus
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| Borna disease virus | ||||||
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| Virus classification | ||||||
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Classification:
ICTVdB Virus Code: 01.081.0.01.001. Virus accession number: 81001001. Obsolete virus code: 81.0.1.0.001; superceded accession number: 81010001. NCBI Taxon Identifier NCBI Taxonomy ID: 12455. Type of the genus: 01.081.0.01 Bornavirus; Family: 01.081 Bornaviridae; Order: 01 Mononegavirales.[1]
Viruses: Group V ssRNA viruses; Order: Mononegavirales; Family: Bornaviridae; Genus: Bornavirus
Description and significance:
A nonsegmented, negative, single-stranded, enveloped RNA virus that is spherical in shape with a total size of 80-125 nm[2] Its core is 50-60 nm in diameter, and its envelope has surface projections approximately 7 nm long that evenly cover the surface.[1]
It is neurotropic and noncytolytic and has a wide geographic distribution and host range.[3] including horses, sheep, and humans. In humans, it causes a range of neurological disorders often characterized by manic-depressive symptoms. Some studies have demonstrated a therapeutic effect of the antiviral agent amantadine in BDV-infected, depressed patients.
BDV research has implications on a wide range of fields from molecular biology and immunology to psychiatry, criminal justice, and education.
Natural Host:
Domain Eucarya, Kingdom Animalia, Phylum Chordata, Subphylum Vertebrata, Class Mammalia and Aves.
Class Aves, Order Struthioniformes, Family Struthionida (ostrich).
Class Mammalia, Order Scandentia, Family Tupaiidae, Genus Tupaia; Order Primates, Family Hominidae, Genus Homo, Species H. sapiens (human); Order Carnivora, Suborder Fissipedia, Family Felidae, Subfamily Felinae, Genus Felis (cats); Order Perissodactyla, Family Equidae, Genus Equus, Species E. caballus (horse); Order Artiodactyla, Family Bovidae, Subfamily Bovinae, Genus Bos, Species B. taurus (cow); Order Artiodactyla, Family Bovidae, Subfamily Caprinae, Genus Ovis, Species O. aries (sheep); Order Rodentia, Suborder Scurognathi, Family Muridae, Subfamily Murinae, Genus Rattus (rat).[1]
When was your organism discovered?
Borna disease was first discovered in horses in Borna, Saxony, Germany in 1763[4] although descriptions of the disease can be traced back to 1660.[5] Borna disease virus was characterized as the causative agent in the early 1900s by Zwick and co-workers in Gieseen, Germany.[3]
How and where was it isolated:
The first cDNA clones of the BDV genome were isolated in the early 1990s by a number of different research groups. Cubitt et al (1994) isolated BDV RNA from the C6 cells of experimentally infected rats at The Scripps Research Institute in La Jolla, California prior to sequencing.[6] Briese et al (1994) similarly obtained clones from rat oligodendrocyte isolates at the University of California, Irvine.[7] The sequence analyses were performed using BDV specific cDNA probes.
Genome structure:
BDV has a ca. 8.9 kb genome size of encapsulated, non-segmented, single-stranded RNA[3][8] with five open reading frames (ORFs).[7] ORFs I-V correspond to a nucleoprotein 40-kDa p40 (N); a phosphoprotein 23-kDa p23 (P); a matrix protein 16-kDa p16 (M); a glycoprotein 57-kDa p57 (G); and an L-polymerase 190-kDa p190 (L), respectively. A sixth protein, p10 (X), has a function that is, as yet, unknown, and its sequence is not homologous to that of the other known Mononegavirales[9] The five ORFs are flanked by 53 nt of noncoding sequence at the 3' terminus and 91 nt of noncoding sequence at the 5' terminus.[7]
The BDV genome is homologous to Filoviridae, Paramyxoviridae, and Rhabdoviridae in both cistronic and extracistronic regions.[7]
Interesting features:
The BDV genome is smaller than that of other negative-strand RNA viruses. Unlike other non-segmented, negative-strand RNA animal viruses and Mononegavirales, BDV replicates and transcribes in the nuclei of its hosts. It has a number of other features that distinguish it from all other Mononegavirales, such as overlap of coding sequence, post-transcriptional modification properties, and alternative splicing in the nuclei of its host.[7] It is also highly unusual in certain aspects of its pathogenesis, including its highly specific localization in the CNS, manipulation of activity-dependent synaptic plasticity, and its chronic persistence in the absence of overt inflammation and cytolysis.[10] As a whole, the BDV genome has a remarkable degree of conservation with less than 6% divergence at the nucleotide level.[9]
How does this organism cause disease?
The pathogenesis of Borna disease is a subject of intense debate.
BDV is assumed to be transmitted through nasal, salival, or conjunctival secretions. It likely gains access to the central nervous system (CNS) via intraaxonal migration through the olfactory nerve or nerve endings in the oropharyngeal and intestinal regions. The virus spreads throughout the CNS by intraaxonal transport and centrifugally into the peripheral nerves.[3]
Some studies have shown that the disease is at least partially mediated by immune system.[11][12] Such models are supported by evidence that immunocompromised Lewis rats do not become ill even when infected with BDV. Several of these reports (i.e. Narayan et al, 1983 and Stiz et al, 1995) suggest that BDV-altered T cell responses contribute to the pathogenesis.
More recent reports (see Current Research) have largely widened the realm of etiological suspects, implicating BDV-mediated effects on synaptic plasticity,[13] PKC pathways,[10] and a widespread array of proteins involved in neuronal signaling.[14]
What makes it biologically interesting?
Its application to Biotechnology... its medical importance... major research findings made with it... what's cool about borna disease virus as an organism:
- Several studies have indicated that BDV-infection may cause obesity in Lewis rats. Herden et al (2000) suggests that BDV infection may stimulate obesity through inflammation and an increase in viral proteins in the hypothalamus, an area of the brain that is often involved in weight gain.
- Many studies have examined the effectiveness of amantadine against BDV. Amantadine was approved by the US Food and Drug Administration for use as a prophylactic against influenza in the 1960s and was shortly thereafter found to reduce symptoms of Parkinson's disease. There is debate among the scientific community as to the usefulness of amantadine as a therapeutic drug in reducing infection and psychiatric symptoms among BDV-infected patients with affective disorders. Some researchers (i.e. Bode et al, 1997; Dietrich et al, 2000; Dietrich and Bode, 2008; Ohlmeier et al, 2008) have found evidence that amantadine significantly reduces mania and depression in these patients. Other studies found no antiviral activity of amantidine on BDV.[15][16]
Current Research:
RNA from Borna disease virus in patients with schizophrenia, schizoaffective patients, and in their biological relatives.[5] This paper investigated Borna disease virus (BDV) p24 RNA prevalence in the blood of psychiatric patients, their biological relatives, and healthy controls. The authors extracted the total RNA from peripheral white blood cells and used RT-nested PCR for amplification of the BDV p24. They sequenced the products and then analyzed the results using information from the National Center for Biotechnology Information (NCBI) NIH database. The BDV p24 was found in 44.4% of patients with schizophrenia or schizoaffective disorder, 50.0% of their biological relatives without mental disorders, 37.5% of their biological relatives with mood disorders, and 14.8% of healthy controls. Patients and their biological relatives without mental disorders were found to be significantly more likely than healthy controls to test positive for the presence of BDV p24 RNA. The results add to a body of literature that suggests a link between BDV infection and neurobehavioral disorders, although the authors contend that BDV is likely only one among many interacting factors that may contribute to an individual's cumulative psychiatric status.
Borna disease virus infection impairs synaptic plasticity.[13] This paper examines the mechanisms through which Borna disease virus (BDV) causes neurobehavioral disorders. The authors took advantage of the newly designed multielectrode arrays (MEA), which consists of a grid of 60 planar electrodes embedded in a culture dish and concentrated on a 1mm square area. They grew both BDV-infected and control neurons in the sterile MEA chamber and stimulated them with bicuculline, a gamma-aminobutyric acid A receptor antagonist that has been shown to result in an increase in synaptic activity at excitatory synapses. Measuring electrophysiological responses in real time, the authors found that BDV has no impact on spontaneous neuronal activity or on the ability of the neurons to modulate synaptic transmission during stimulation. However, the researchers found significant differences between experimental and control neurons 1 hour post-stimulus. The control neurons maintained a high level of activity following bicuculline exposure 1 and 2 hours after stimulus, while the BDV-infected neurons had returned to basal levels. Because this post-stimulus activation increases the strength of synapatic connections and is implicated in processes associated with learning and memory, the results suggest that the neurobehavioral changes associated with BDV-infections may be a result of an impairment in synaptic plasticity.
Borna disease virus blocks potentiation of presynaptic activity through inhibition of protein kinase C signaling.[10] Since previous studies have demonstrated Borna disease virus (BDV)-infection to be associated with neurobehavioral disorders, the study investigated whether BDV has a deleterious effect on synaptic signaling. Protein kinases are known to have important roles in the early stages of synaptic signaling, so the researchers used Western blot analyses with phospho-specific antibodies to examine whether BDV-infections were associated with impairments in the functioning of extracellular-regulated kinase (ERK) 1/2, protein kinase A (PKA), calcium/calmodulin dependent kinase (CaMK) II, and PKC phosphorylate presynaptic proteins that modulate synaptic vesicle recycling. The researchers found no effect of BDV-infection on ERK 1/2, PKA, and CaMK II, but the phosphorylation of two major PKC substrates, myristoylated alanine-rich C kinase substrate (MARCKS) and Munc18-1/nSec1 (Munch18), was severely inhibited in BDV-infected neurons, indicating BDV interference with PKC signaling.
The authors followed with a number of related findings that shed light on the mechanisms whereby BDV might have an effect on the PKC signaling pathway. They discovered that BDV had no affect on the physical translocation of several different forms of PKC from the cytosol to membranes. Since this process plays a major role in the activation of PKC, the authors concluded that BDV-mediated effects on PKC signaling take place downstream of PKC activation. In another experiment, the authors also used vectors to express BDV phosphoprotein (BDV P) in non-infected neuronal tissue. They found that simply the expression of BDV P was sufficient to significantly decrease the phosphorylation of PKC substrates, suggesting that BDV's inhibition of PKC signaling may involve a mechanism whereby its phosphoprotein competes with the substrates of PKC for phosphorylation. Lastly, the study found that similar effects of PKA agonist forskolin on infected and control neurons, confirming that it is the PKC and not the cAMP/PKA pathway that is affected by BDV.
Proteomic analysis reveals selective impediment of neuronal remodeling upon Borna disease virus infection.[14] This study set out to explore differences in the proteomes of neurons infected with Borna disease virus (BDV) and non-infected controls. Control and infected cerebral cortical neurons were generated from embryonic Sprague-Dawley rats, fractionated with two-dimensional liquid chromatography (2D-LC), and their respective proteins identified and analyzed using nano-liquid chromatography (nanoLC)-tandem mass spectrometry (MS/MS). The analyses revealed BDV impairment of proteins involved in synaptic activity (changes in B-FABP, differences for MARCKS and mUNC18, significant downregulation of GAP-43, significant decrease in synapsin 1 levels); cytoskeleton dynamics (differences in 10 of the 28 actin-binding proteins and 5 of the 13 microtubule-binding proteins that are known to be associated with the neuronal core); mRNA regulation (significant decrease in MeCP2 levels); and mRNA expression (acetylation of the Histone H2B protein). The lack of evidence for a change in gross neuronal morphology is consistent with previous studies, and the paper suggests that the BDV alteration of proteins involved in neuronal signaling represents an overall strategy for long term survival and propagation of the virus.
References:
- ↑ 1.0 1.1 1.2 Buchen-Osmond, C. (Ed) (2003). 01.081.0.01.001. Borna disease virus. In: ICTVdB - The Universal Virus Database, version 3. Buchen-Osmond, C. (Ed), ICTVdB Management, Columbia University, New York, USA.
- ↑ Brooks, G.F., Butel, J.S., and Morse, S.A. (2001). Jawetz, Melnick, and Adelberg's Medical Microbiology, 22nd Edition. New York: McGraw-Hill. 320.
- ↑ 3.0 3.1 3.2 3.3 Richt, J.A., Pfeuffer, I., Christ, M., Frese, K., Bechter, K., Herzog, S. (1997). Borna disease virus infection in animals and humans. Emerging Infectious Diseases, 3(3). 343-352.
- ↑ Durrwald, L. (1997). Journal of Veterinary Medicine, 44. 147-184.
- ↑ 5.0 5.1 Nunes, S.O.V., Itano, E.N., Amarante, M.K., Reiche, E.M.V., Miranda, H.C., de Oliveira, C.E.C., Matsuo, T., Vargas, H.O., Watanabe, M.A.E. (2008). RNA from Borna disease virus in patients with schizophrenia, schizoaffective patients, and in their biological relatives. Journal of Clinical Laboratory Analysis, 22. 314-320.
- ↑ Cubitt, B., Oldstone, C., and de la Torre, J.C. (1994). Sequence and genome organization of Borna disease virus. Journal of Virology, 68(3). 1382-1396.
- ↑ 7.0 7.1 7.2 7.3 7.4 Briese, T., Schneemann, A., Lewis, A., Park, Y., Kim, H., Ludwig, H., and Lipkin, I. (1994). Genomic organization of Borna disease virus. Proceedings of the National Academy of Sciences, 91(10). 4362-66.
- ↑ de la Torre, J.C. (1994). Molecular biology of Borna Disease Virus: Prototype of a new group of animal viruses. Journal of Virology, 68(12). 7669-75.
- ↑ 9.0 9.1 Hornig, M., Briese, T., and Lipkin, W.I. (2003). Borna disease virus. Journal of NeuroVirology, 9. 259-79.
- ↑ 10.0 10.1 10.2 Volmer, R., Monnet, C., and Gonzalez-Dunia, D. (2006). Borna disease virus blocks potentiation of presynaptic activity through inhibition of protein kinase C signaling. PLoS Pathogens, 2(3). e19.
- ↑ Narayan, O., Herzog, S., Frese, K., Scheefers, H., and Rott, R. (1983). Behavioral disease in rats caused by immunopathological responses to persistent Borna visu in the brain. Science, 220(1). 401-3.
- ↑ Stitz, L., Dietzshold, B., and Carbone, K.M. (1995). Immunopathogenesis of Borna disease. Current Topics in Microbiology and Immunology, 190. 75-92.
- ↑ 13.0 13.1 Volmer, R., Prat, C.M.A., Le Masson, G., Garenne, A., and Gonzalez-Dunia, D. (2007). Borna disease virus infection impairs synaptic plasticity. Journal of Virology, 81(16). 8833-7.
- ↑ 14.0 14.1 Suberbielle, E., Stella, A., Pont, F., Monnet, C., Mouton, E., Lamouroux, L., Monsarrat, B., Gonzalez-Dunia, D. (2008). Proteomic analysis reveals selective impediment of neuronal remodeling upon Borna disease virus infection. Journal of Virology, 82(24). 12265-12279.
- ↑ Cubitt, B., and de la Torre, J.C. (1997). Amantadine does not have antiviral activity against Borna disease. Archives of Virology, 142(10). 2035-42.
- ↑ Hallensleben, W., Zocher, M., and Staecheli, P. (1997). Borna disease virus is not sensitive to amantadine. Archives of Virology, 142(10). 2043-8.