Borna disease virus: Difference between revisions
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'''Borna disease virus infection impairs synaptic plasticity.'''<ref>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.</ref> This paper examines the mechanisms through which 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 infection impairs synaptic plasticity.'''<ref>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.</ref> This paper examines the mechanisms through which 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.'''<ref>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.</ref> Since previous studies have demonstrated 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, 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. | '''Borna disease virus blocks potentiation of presynaptic activity through inhibition of protein kinase C signaling.'''<ref>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.</ref> Since previous studies have demonstrated 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 found 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 in non-infected neuronal tissue. They found that simply the expression of BDV phosphoprotein 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 confirm that it is the PKC and not the cAMP/PKA pathway that is affected by BDV. | 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 found 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 in non-infected neuronal tissue. They found that simply the expression of BDV phosphoprotein 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 confirm that it is the PKC and not the cAMP/PKA pathway that is affected by BDV. | ||
== References: == | == References: == | ||
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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 80-125nm[2] Its core is 50-60nm in diameter, and its envelope has surface projections approximately 7nm 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 ranging from encephalitis[4] to manic-depressive symptoms. Some studies have demonstrated a therapeutic effect of the antiviral agent amantadine in BDV-infected, depressed patients.
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.[5], but Borna disease virus was only characterized as the causative agent in the early 1900s by Zwick and co-workers in Gieseen, Germany.[3]
How and where was it isolated:
Genome structure:
BDV has a ca. 8.9 kb genome size of encapsulated, non-segmented, single-stranded RNA[3][6] with six open reading frames (ORFs).[7] ORFs I, II, and III correspond to 40-kDa p40, 24-kDa p24, and 14.5-kDa p14.5 BDV proteins, respectively.[6] ORF IV and V are capable of encoding 56-kDa and 180-kDa proteins, respectively, but these have not yet been identified.[6] 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:
Unlike other non-segmented negative-strand RNA animal viruses, BDV replicates and transcribes in the nuclei of its hosts.[7] BDV is also unique among known Mononegavirales in that it uses cellular splicing machinery to generate some of its mRNAs.[8]
How does this organism cause disease?
The virus is assumed to be transmitted through nasal, salival, or conjunctival secretions.[3]
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]
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:
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.[9][10]
Current Research:
Borna disease virus infection impairs synaptic plasticity.[11] This paper examines the mechanisms through which 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.[12] Since previous studies have demonstrated 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 found 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 in non-infected neuronal tissue. They found that simply the expression of BDV phosphoprotein 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 confirm that it is the PKC and not the cAMP/PKA pathway that is affected by BDV.
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 3.4 Richt, J.A., Pfeuffer, I., Christ, M., Frese, K., Bechter, K., Herzog, S. Borna disease virus infection in animals and humans. Emerging Infectious Diseases, 3(3). 1997: 343-352.
- ↑ Bode, L., Ludwig, H. Clinical similarities and close genetic relationship of human and animal Borna disease virus. Archives of Virology Supplement, 13. 1997: 167-82
- ↑ Durrwald, L. (1997). Journal of Veterinary Medicine, 44. 147-184.
- ↑ 6.0 6.1 6.2 de la Torre, J.C. Molecular biology of Borna Disease Virus: Prototype of a new group of animal viruses. Journal of Virology, 68(12). 1994: 7669-75.
- ↑ 7.0 7.1 7.2 7.3 Briese, T., Schneemann, A., Lewis, A., Park, Y., Kim, H., Ludwig, H., and Lipkin, I. Genomic organization of Borna disease virus. Proceedings of the National Academy of Sciences, 91(10). 1994: 4362-66.
- ↑ Hornig, M., Briese, T., and Lipkin, W.I. (2003). Borna disease virus. Journal of NeuroVirology, 9. 259-79.
- ↑ 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.
- ↑ 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.
- ↑ 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.