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Michael D. Baron - One of the best experts on this subject based on the ideXlab platform.
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Dugbe Virus ovarian tumour domain interferes with ubiquitin isg15 regulated innate immune cell signalling
Journal of General Virology, 2013Co-Authors: Siddharth Bakshi, Anne Bridgen, Barbara Holzer, Geoffrey Mcmullan, Daniel Quinn, Michael D. BaronAbstract:The ovarian tumour (OTU) domain of the nairoVirus L protein has been shown to remove ubiquitin and interferon-stimulated gene 15 protein (ISG15) from host cell proteins, which is expected to have multiple effects on cell signalling pathways. We have confirmed that the OTU domain from the L protein of the apathogenic nairoVirus Dugbe Virus has deubiquitinating and deISGylating activity and shown that, when expressed in cells, it is highly effective at blocking the TNF-α/NF-κB and interferon/JAK/STAT signalling pathways even at low doses. Point mutations of the catalytic site of the OTU [C40A, H151A and a double mutant] both abolished the ability of the OTU domain to deubiquitinate and deISGylate proteins and greatly reduced its effect on cell signalling pathways, confirming that it is this enzymic activity that is responsible for blocking the two signalling pathways. Expression of the inactive mutants at high levels could still block signalling, suggesting that the viral OTU can still bind to its substrate even when mutated at its catalytic site. The nairoVirus L protein is a very large protein that is normally confined to the cytoplasm, where the Virus replicates. When the OTU domain was prevented from entering the nucleus by expressing it as part of the N-terminal 205 kDa of the viral L protein, it continued to block type I interferon signalling, but no longer blocked the TNF-α-induced activation of NF-κB.
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inhibition of interferon induction and action by the nairoVirus nairobi sheep disease Virus ganjam Virus
PLOS ONE, 2011Co-Authors: Barbara M Holzer, Siddharth Bakshi, Anne Bridgen, Michael D. BaronAbstract:The NairoViruses are an important group of tick-borne Viruses that includes pathogens of man (Crimean Congo hemorrhagic fever Virus) and livestock animals (Dugbe Virus, Nairobi sheep disease Virus (NSDV)). NSDV is found in large parts of East Africa and the Indian subcontinent (where it is known as Ganjam Virus). We have investigated the ability of NSDV to antagonise the induction and actions of interferon. Both pathogenic and apathogenic isolates could actively inhibit the induction of type 1 interferon, and also blocked the signalling pathways of both type 1 and type 2 interferons. Using transient expression of viral proteins or sections of viral proteins, these activities all mapped to the ovarian tumour-like protease domain (OTU) found in the viral RNA polymerase. Virus infection, or expression of this OTU domain in transfected cells, led to a great reduction in the incorporation of ubiquitin or ISG15 protein into host cell proteins. Point mutations in the OTU that inhibited the protease activity also prevented it from antagonising interferon induction and action. Interestingly, a mutation at a peripheral site, which had little apparent effect on the ability of the OTU to inhibit ubiquitination and ISG15ylation, removed the ability of the OTU to block the induction of type 1 and the action of type 2 interferons, but had a lesser effect on the ability to block type 1 interferon action, suggesting that targets other than ubiquitin and ISG15 may be involved in the actions of the viral OTU.
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Inhibition of Interferon Induction and Action by the NairoVirus Nairobi Sheep Disease Virus/Ganjam Virus
PLOS ONE, 2011Co-Authors: Barbara M Holzer, Siddharth Bakshi, Anne Bridgen, Michael D. BaronAbstract:The NairoViruses are an important group of tick-borne Viruses that includes pathogens of man (Crimean Congo hemorrhagic fever Virus) and livestock animals (Dugbe Virus, Nairobi sheep disease Virus (NSDV)). NSDV is found in large parts of East Africa and the Indian subcontinent (where it is known as Ganjam Virus). We have investigated the ability of NSDV to antagonise the induction and actions of interferon. Both pathogenic and apathogenic isolates could actively inhibit the induction of type 1 interferon, and also blocked the signalling pathways of both type 1 and type 2 interferons. Using transient expression of viral proteins or sections of viral proteins, these activities all mapped to the ovarian tumour-like protease domain (OTU) found in the viral RNA polymerase. Virus infection, or expression of this OTU domain in transfected cells, led to a great reduction in the incorporation of ubiquitin or ISG15 protein into host cell proteins. Point mutations in the OTU that inhibited the protease activity also prevented it from antagonising interferon induction and action. Interestingly, a mutation at a peripheral site, which had little apparent effect on the ability of the OTU to inhibit ubiquitination and ISG15ylation, removed the ability of the OTU to block the induction of type 1 and the action of type 2 interferons, but had a lesser effect on the ability to block type 1 interferon action, suggesting that targets other than ubiquitin and ISG15 may be involved in the actions of the viral OTU.
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Inhibition of Interferon Induction and Action by the NairoVirus Nairobi Sheep Disease Virus/Ganjam Virus
2011Co-Authors: Barbara Holzer, Siddharth Bakshi, Anne Bridgen, Michael D. BaronAbstract:The NairoViruses are an important group of tick-borne Viruses that includes pathogens of man (Crimean Congo hemorrhagic fever Virus) and livestock animals (Dugbe Virus, Nairobi sheep disease Virus (NSDV)). NSDV is found in large parts of East Africa and the Indian subcontinent (where it is known as Ganjam Virus). We have investigated the ability of NSDV to antagonise the induction and actions of interferon. Both pathogenic and apathogenic isolates could actively inhibit the induction of type 1 interferon, and also blocked the signalling pathways of both type 1 and type 2 interferons. Using transient expression of viral proteins or sections of viral proteins, these activities all mapped to the ovarian tumour-like protease domain (OTU) found in the viral RNA polymerase. Virus infection, or expression of this OTU domain in transfected cells, led to a great reduction in the incorporation of ubiquitin or ISG15 protein into host cell proteins. Point mutations in the OTU that inhibited the protease activity also prevented it from antagonising interferon induction and action. Interestingly, a mutation at a peripheral site, which had little apparent effect on the ability of the OTU to inhibit ubiquitination and ISG15ylation, removed the ability of the OTU to block the induction of type 1 and the action of type 2 interferons, but had a lesser effect on the ability to block type 1 interferon action, suggesting that targets other tha
Anne Bridgen - One of the best experts on this subject based on the ideXlab platform.
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Dugbe Virus ovarian tumour domain interferes with ubiquitin isg15 regulated innate immune cell signalling
Journal of General Virology, 2013Co-Authors: Siddharth Bakshi, Anne Bridgen, Barbara Holzer, Geoffrey Mcmullan, Daniel Quinn, Michael D. BaronAbstract:The ovarian tumour (OTU) domain of the nairoVirus L protein has been shown to remove ubiquitin and interferon-stimulated gene 15 protein (ISG15) from host cell proteins, which is expected to have multiple effects on cell signalling pathways. We have confirmed that the OTU domain from the L protein of the apathogenic nairoVirus Dugbe Virus has deubiquitinating and deISGylating activity and shown that, when expressed in cells, it is highly effective at blocking the TNF-α/NF-κB and interferon/JAK/STAT signalling pathways even at low doses. Point mutations of the catalytic site of the OTU [C40A, H151A and a double mutant] both abolished the ability of the OTU domain to deubiquitinate and deISGylate proteins and greatly reduced its effect on cell signalling pathways, confirming that it is this enzymic activity that is responsible for blocking the two signalling pathways. Expression of the inactive mutants at high levels could still block signalling, suggesting that the viral OTU can still bind to its substrate even when mutated at its catalytic site. The nairoVirus L protein is a very large protein that is normally confined to the cytoplasm, where the Virus replicates. When the OTU domain was prevented from entering the nucleus by expressing it as part of the N-terminal 205 kDa of the viral L protein, it continued to block type I interferon signalling, but no longer blocked the TNF-α-induced activation of NF-κB.
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inhibition of interferon induction and action by the nairoVirus nairobi sheep disease Virus ganjam Virus
PLOS ONE, 2011Co-Authors: Barbara M Holzer, Siddharth Bakshi, Anne Bridgen, Michael D. BaronAbstract:The NairoViruses are an important group of tick-borne Viruses that includes pathogens of man (Crimean Congo hemorrhagic fever Virus) and livestock animals (Dugbe Virus, Nairobi sheep disease Virus (NSDV)). NSDV is found in large parts of East Africa and the Indian subcontinent (where it is known as Ganjam Virus). We have investigated the ability of NSDV to antagonise the induction and actions of interferon. Both pathogenic and apathogenic isolates could actively inhibit the induction of type 1 interferon, and also blocked the signalling pathways of both type 1 and type 2 interferons. Using transient expression of viral proteins or sections of viral proteins, these activities all mapped to the ovarian tumour-like protease domain (OTU) found in the viral RNA polymerase. Virus infection, or expression of this OTU domain in transfected cells, led to a great reduction in the incorporation of ubiquitin or ISG15 protein into host cell proteins. Point mutations in the OTU that inhibited the protease activity also prevented it from antagonising interferon induction and action. Interestingly, a mutation at a peripheral site, which had little apparent effect on the ability of the OTU to inhibit ubiquitination and ISG15ylation, removed the ability of the OTU to block the induction of type 1 and the action of type 2 interferons, but had a lesser effect on the ability to block type 1 interferon action, suggesting that targets other than ubiquitin and ISG15 may be involved in the actions of the viral OTU.
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Inhibition of Interferon Induction and Action by the NairoVirus Nairobi Sheep Disease Virus/Ganjam Virus
PLOS ONE, 2011Co-Authors: Barbara M Holzer, Siddharth Bakshi, Anne Bridgen, Michael D. BaronAbstract:The NairoViruses are an important group of tick-borne Viruses that includes pathogens of man (Crimean Congo hemorrhagic fever Virus) and livestock animals (Dugbe Virus, Nairobi sheep disease Virus (NSDV)). NSDV is found in large parts of East Africa and the Indian subcontinent (where it is known as Ganjam Virus). We have investigated the ability of NSDV to antagonise the induction and actions of interferon. Both pathogenic and apathogenic isolates could actively inhibit the induction of type 1 interferon, and also blocked the signalling pathways of both type 1 and type 2 interferons. Using transient expression of viral proteins or sections of viral proteins, these activities all mapped to the ovarian tumour-like protease domain (OTU) found in the viral RNA polymerase. Virus infection, or expression of this OTU domain in transfected cells, led to a great reduction in the incorporation of ubiquitin or ISG15 protein into host cell proteins. Point mutations in the OTU that inhibited the protease activity also prevented it from antagonising interferon induction and action. Interestingly, a mutation at a peripheral site, which had little apparent effect on the ability of the OTU to inhibit ubiquitination and ISG15ylation, removed the ability of the OTU to block the induction of type 1 and the action of type 2 interferons, but had a lesser effect on the ability to block type 1 interferon action, suggesting that targets other than ubiquitin and ISG15 may be involved in the actions of the viral OTU.
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Inhibition of Interferon Induction and Action by the NairoVirus Nairobi Sheep Disease Virus/Ganjam Virus
2011Co-Authors: Barbara Holzer, Siddharth Bakshi, Anne Bridgen, Michael D. BaronAbstract:The NairoViruses are an important group of tick-borne Viruses that includes pathogens of man (Crimean Congo hemorrhagic fever Virus) and livestock animals (Dugbe Virus, Nairobi sheep disease Virus (NSDV)). NSDV is found in large parts of East Africa and the Indian subcontinent (where it is known as Ganjam Virus). We have investigated the ability of NSDV to antagonise the induction and actions of interferon. Both pathogenic and apathogenic isolates could actively inhibit the induction of type 1 interferon, and also blocked the signalling pathways of both type 1 and type 2 interferons. Using transient expression of viral proteins or sections of viral proteins, these activities all mapped to the ovarian tumour-like protease domain (OTU) found in the viral RNA polymerase. Virus infection, or expression of this OTU domain in transfected cells, led to a great reduction in the incorporation of ubiquitin or ISG15 protein into host cell proteins. Point mutations in the OTU that inhibited the protease activity also prevented it from antagonising interferon induction and action. Interestingly, a mutation at a peripheral site, which had little apparent effect on the ability of the OTU to inhibit ubiquitination and ISG15ylation, removed the ability of the OTU to block the induction of type 1 and the action of type 2 interferons, but had a lesser effect on the ability to block type 1 interferon action, suggesting that targets other tha
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Short Communication Pathogenesis of Dugbe Virus infection in wild-type and interferon-deficient mice
2009Co-Authors: Amanda Boyd, John K. Fazakerley, Anne BridgenAbstract:In 129 mice, infection with the nairoVirus Dugbe Virus (DUGV) was lethal following intracerebral but not intraperitoneal inoculation. Following both routes of inoculation, immunostaining of tissue sections demonstrated Virus-positive cells in the brain, indicating that DUGV is neuroinvasive in mice. Many brain areas were affected and neurones were the main cell type infected. Infected cells showed punctate accumulations of viral nucleoprotein in the cytoplasm, indicative of Virus replication sites. Immunostaining for activated caspase 3 demonstrated no evidence of apoptosis. The type I interferon (IFN) system plays a significant role in defence against DUGV, as 129 IFN-a/b R ”/” mice died rapidly following both intraperitoneal and intracerebral inoculations. Studies
Stuart T. Nichol - One of the best experts on this subject based on the ideXlab platform.
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Crimean–Congo hemorrhagic fever Virus genome L RNA segment and encoded protein
Virology, 2004Co-Authors: Jessica E. Honig, Jane C. Osborne, Stuart T. NicholAbstract:Abstract Sequence analysis of the L RNA genome segment and predicted encoded L polymerase protein of Crimean–Congo hemorrhagic fever (CCHF) Virus (genus NairoVirus, family Bunyaviridae) demonstrates that they are approximately twice the size of those found in Viruses of other bunyaVirus genera. The CCHF Virus L segment and encoded protein (12164 nucleotides and 3944 amino acids, respectively) are similar in size and sequence to those of the nairoVirus Dugbe Virus (12255/62% and 4036/62% nucleotide and amino acid length/identity, respectively). The identification of an ovarian tumor (OTU)-like protease motif in the L protein amino termini of the nairoViruses Dugbe, CCHF, and Nairobi sheep disease (NSD) indicates these proteins are members of the recently described OTU-like protease family and suggests that these large proteins may be polyproteins that are autoproteolytically cleaved or involved in deubiquitination.
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Nairobi sheep disease Virus, an important tick-borne pathogen of sheep and goats in Africa, is also present in Asia.
Virology, 2002Co-Authors: Beate I. Marczinke, Stuart T. NicholAbstract:Nairobi sheep disease (NSD) Virus is the prototype of the tick-borne NSD serogroup, genus NairoVirus, family Bunyaviridae. It is highly pathogenic for sheep and goats, causes disease in humans, and is widespread throughout East Africa. Ganjam Virus has caused disease in goats and humans in India. Due to their occurrence on different continents and association with different ticks, these Viruses were considered distinct despite serologic cross-reactivity. Their S RNA genome segments and encoded nucleocapsid proteins were found to be 1590 nucleotides and 482 amino acids in length and differed by only 10 and 3% at nucleotide and amino acid levels, respectively. Genetic and serologic data demonstrate that Ganjam Virus is an Asian variant of NSD Virus. These Viruses were phylogenetically more closely related to Hazara Virus than Dugbe Virus.
Siddharth Bakshi - One of the best experts on this subject based on the ideXlab platform.
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Dugbe Virus ovarian tumour domain interferes with ubiquitin isg15 regulated innate immune cell signalling
Journal of General Virology, 2013Co-Authors: Siddharth Bakshi, Anne Bridgen, Barbara Holzer, Geoffrey Mcmullan, Daniel Quinn, Michael D. BaronAbstract:The ovarian tumour (OTU) domain of the nairoVirus L protein has been shown to remove ubiquitin and interferon-stimulated gene 15 protein (ISG15) from host cell proteins, which is expected to have multiple effects on cell signalling pathways. We have confirmed that the OTU domain from the L protein of the apathogenic nairoVirus Dugbe Virus has deubiquitinating and deISGylating activity and shown that, when expressed in cells, it is highly effective at blocking the TNF-α/NF-κB and interferon/JAK/STAT signalling pathways even at low doses. Point mutations of the catalytic site of the OTU [C40A, H151A and a double mutant] both abolished the ability of the OTU domain to deubiquitinate and deISGylate proteins and greatly reduced its effect on cell signalling pathways, confirming that it is this enzymic activity that is responsible for blocking the two signalling pathways. Expression of the inactive mutants at high levels could still block signalling, suggesting that the viral OTU can still bind to its substrate even when mutated at its catalytic site. The nairoVirus L protein is a very large protein that is normally confined to the cytoplasm, where the Virus replicates. When the OTU domain was prevented from entering the nucleus by expressing it as part of the N-terminal 205 kDa of the viral L protein, it continued to block type I interferon signalling, but no longer blocked the TNF-α-induced activation of NF-κB.
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inhibition of interferon induction and action by the nairoVirus nairobi sheep disease Virus ganjam Virus
PLOS ONE, 2011Co-Authors: Barbara M Holzer, Siddharth Bakshi, Anne Bridgen, Michael D. BaronAbstract:The NairoViruses are an important group of tick-borne Viruses that includes pathogens of man (Crimean Congo hemorrhagic fever Virus) and livestock animals (Dugbe Virus, Nairobi sheep disease Virus (NSDV)). NSDV is found in large parts of East Africa and the Indian subcontinent (where it is known as Ganjam Virus). We have investigated the ability of NSDV to antagonise the induction and actions of interferon. Both pathogenic and apathogenic isolates could actively inhibit the induction of type 1 interferon, and also blocked the signalling pathways of both type 1 and type 2 interferons. Using transient expression of viral proteins or sections of viral proteins, these activities all mapped to the ovarian tumour-like protease domain (OTU) found in the viral RNA polymerase. Virus infection, or expression of this OTU domain in transfected cells, led to a great reduction in the incorporation of ubiquitin or ISG15 protein into host cell proteins. Point mutations in the OTU that inhibited the protease activity also prevented it from antagonising interferon induction and action. Interestingly, a mutation at a peripheral site, which had little apparent effect on the ability of the OTU to inhibit ubiquitination and ISG15ylation, removed the ability of the OTU to block the induction of type 1 and the action of type 2 interferons, but had a lesser effect on the ability to block type 1 interferon action, suggesting that targets other than ubiquitin and ISG15 may be involved in the actions of the viral OTU.
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Inhibition of Interferon Induction and Action by the NairoVirus Nairobi Sheep Disease Virus/Ganjam Virus
PLOS ONE, 2011Co-Authors: Barbara M Holzer, Siddharth Bakshi, Anne Bridgen, Michael D. BaronAbstract:The NairoViruses are an important group of tick-borne Viruses that includes pathogens of man (Crimean Congo hemorrhagic fever Virus) and livestock animals (Dugbe Virus, Nairobi sheep disease Virus (NSDV)). NSDV is found in large parts of East Africa and the Indian subcontinent (where it is known as Ganjam Virus). We have investigated the ability of NSDV to antagonise the induction and actions of interferon. Both pathogenic and apathogenic isolates could actively inhibit the induction of type 1 interferon, and also blocked the signalling pathways of both type 1 and type 2 interferons. Using transient expression of viral proteins or sections of viral proteins, these activities all mapped to the ovarian tumour-like protease domain (OTU) found in the viral RNA polymerase. Virus infection, or expression of this OTU domain in transfected cells, led to a great reduction in the incorporation of ubiquitin or ISG15 protein into host cell proteins. Point mutations in the OTU that inhibited the protease activity also prevented it from antagonising interferon induction and action. Interestingly, a mutation at a peripheral site, which had little apparent effect on the ability of the OTU to inhibit ubiquitination and ISG15ylation, removed the ability of the OTU to block the induction of type 1 and the action of type 2 interferons, but had a lesser effect on the ability to block type 1 interferon action, suggesting that targets other than ubiquitin and ISG15 may be involved in the actions of the viral OTU.
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Inhibition of Interferon Induction and Action by the NairoVirus Nairobi Sheep Disease Virus/Ganjam Virus
2011Co-Authors: Barbara Holzer, Siddharth Bakshi, Anne Bridgen, Michael D. BaronAbstract:The NairoViruses are an important group of tick-borne Viruses that includes pathogens of man (Crimean Congo hemorrhagic fever Virus) and livestock animals (Dugbe Virus, Nairobi sheep disease Virus (NSDV)). NSDV is found in large parts of East Africa and the Indian subcontinent (where it is known as Ganjam Virus). We have investigated the ability of NSDV to antagonise the induction and actions of interferon. Both pathogenic and apathogenic isolates could actively inhibit the induction of type 1 interferon, and also blocked the signalling pathways of both type 1 and type 2 interferons. Using transient expression of viral proteins or sections of viral proteins, these activities all mapped to the ovarian tumour-like protease domain (OTU) found in the viral RNA polymerase. Virus infection, or expression of this OTU domain in transfected cells, led to a great reduction in the incorporation of ubiquitin or ISG15 protein into host cell proteins. Point mutations in the OTU that inhibited the protease activity also prevented it from antagonising interferon induction and action. Interestingly, a mutation at a peripheral site, which had little apparent effect on the ability of the OTU to inhibit ubiquitination and ISG15ylation, removed the ability of the OTU to block the induction of type 1 and the action of type 2 interferons, but had a lesser effect on the ability to block type 1 interferon action, suggesting that targets other tha
Barbara M Holzer - One of the best experts on this subject based on the ideXlab platform.
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inhibition of interferon induction and action by the nairoVirus nairobi sheep disease Virus ganjam Virus
PLOS ONE, 2011Co-Authors: Barbara M Holzer, Siddharth Bakshi, Anne Bridgen, Michael D. BaronAbstract:The NairoViruses are an important group of tick-borne Viruses that includes pathogens of man (Crimean Congo hemorrhagic fever Virus) and livestock animals (Dugbe Virus, Nairobi sheep disease Virus (NSDV)). NSDV is found in large parts of East Africa and the Indian subcontinent (where it is known as Ganjam Virus). We have investigated the ability of NSDV to antagonise the induction and actions of interferon. Both pathogenic and apathogenic isolates could actively inhibit the induction of type 1 interferon, and also blocked the signalling pathways of both type 1 and type 2 interferons. Using transient expression of viral proteins or sections of viral proteins, these activities all mapped to the ovarian tumour-like protease domain (OTU) found in the viral RNA polymerase. Virus infection, or expression of this OTU domain in transfected cells, led to a great reduction in the incorporation of ubiquitin or ISG15 protein into host cell proteins. Point mutations in the OTU that inhibited the protease activity also prevented it from antagonising interferon induction and action. Interestingly, a mutation at a peripheral site, which had little apparent effect on the ability of the OTU to inhibit ubiquitination and ISG15ylation, removed the ability of the OTU to block the induction of type 1 and the action of type 2 interferons, but had a lesser effect on the ability to block type 1 interferon action, suggesting that targets other than ubiquitin and ISG15 may be involved in the actions of the viral OTU.
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Inhibition of Interferon Induction and Action by the NairoVirus Nairobi Sheep Disease Virus/Ganjam Virus
PLOS ONE, 2011Co-Authors: Barbara M Holzer, Siddharth Bakshi, Anne Bridgen, Michael D. BaronAbstract:The NairoViruses are an important group of tick-borne Viruses that includes pathogens of man (Crimean Congo hemorrhagic fever Virus) and livestock animals (Dugbe Virus, Nairobi sheep disease Virus (NSDV)). NSDV is found in large parts of East Africa and the Indian subcontinent (where it is known as Ganjam Virus). We have investigated the ability of NSDV to antagonise the induction and actions of interferon. Both pathogenic and apathogenic isolates could actively inhibit the induction of type 1 interferon, and also blocked the signalling pathways of both type 1 and type 2 interferons. Using transient expression of viral proteins or sections of viral proteins, these activities all mapped to the ovarian tumour-like protease domain (OTU) found in the viral RNA polymerase. Virus infection, or expression of this OTU domain in transfected cells, led to a great reduction in the incorporation of ubiquitin or ISG15 protein into host cell proteins. Point mutations in the OTU that inhibited the protease activity also prevented it from antagonising interferon induction and action. Interestingly, a mutation at a peripheral site, which had little apparent effect on the ability of the OTU to inhibit ubiquitination and ISG15ylation, removed the ability of the OTU to block the induction of type 1 and the action of type 2 interferons, but had a lesser effect on the ability to block type 1 interferon action, suggesting that targets other than ubiquitin and ISG15 may be involved in the actions of the viral OTU.
