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David M Haig - One of the best experts on this subject based on the ideXlab platform.
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Complete sequence and analysis of the ovine Herpesvirus 2 genome.
The Journal of general virology, 2020Co-Authors: Jane Hart, David M Haig, Mathias Ackermann, Gamini Jayawardane, George Russell, Hugh Reid, James P StewartAbstract:Ovine Herpesvirus 2 (OvHV-2) is endemic in sheep populations worldwide and causes malignant catarrhal fever (MCF), a lymphoproliferative disease, in cattle, bison and deer. OvHV-2 has been placed in the gammaHerpesvirus subfamily and is related closely to Alcelaphine Herpesvirus 1 (AlHV-1). Here, the cloning, sequencing and analysis of the complete OvHV-2 genome derived from a lymphoblastoid cell line from an affected cow (BJ1035) are reported. The unique portion of the genome consists of 130,930 bp, with a mean G+C content of 52 mol%. The unique DNA is flanked by multiple copies of terminal repeat elements 4205 bp in length, with a mean G+C content of 72 mol%. Analysis revealed 73 open reading frames (ORFs), the majority (62) of which showed homology to other gammaHerpesvirus genes. A further subset of nine ORFs is shared with only the related AlHV-1. Three ORFs are entirely unique to OvHV-2, including a spliced homologue of cellular interleukin-10 that retains the exon structure of the cellular gene. The sequence of OvHV-2 is a critical first step in the study of the pathogenesis and treatment of MCF.
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Alcelaphine Herpesvirus 1 glycoprotein B: recombinant expression and antibody recognition
Archives of Virology, 2016Co-Authors: Helen Todd, David M Haig, Neil F Inglis, David Deane, Ann Percival, Kevin Mclean, Erin D. T. Manson, Shilpa Nayuni, Lindsey M. Hutt-fletcher, Dawn M. GrantAbstract:The gammaHerpesvirus Alcelaphine Herpesvirus 1 (AlHV-1) causes fatal malignant catarrhal fever (MCF) in susceptible species including cattle, but infects its reservoir host, wildebeest, without causing disease. Pathology in cattle may be influenced by virus-host cell interactions mediated by the virus glycoproteins. Cloning and expression of a haemagglutinin-tagged version of the AlHV-1 glycoprotein B (gB) was used to demonstrate that the AlHV-1-specific monoclonal antibody 12B5 recognised gB and that gB was the main component of the gp115 complex of AlHV-1, a glycoprotein complex of five components identified on the surface of AlHV-1 by immunoprecipitation and radiolabelling. Analysis of AlHV-1 virus particles showed that the native form of gB was detected by mAb 12B5 as a band of about 70 kDa, whilst recombinant gB expressed by transfected HEK293T cells appeared to be subject to additional cleavage and incomplete post-translational processing. Antibody 12B5 recognised an epitope on the N-terminal furin-cleaved fragment of gB on AlHV-1 virus particles. It could be used to detect recombinant and virus-expressed gB on western blots and on the surface of infected cells by flow cytometry, whilst recombinant gB was detected on the surface of transfected cells by immunofluorescence. Recombinant gB has potential as an antigen for ELISA detection of MCF virus infection and as a candidate vaccine antigen.
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Alcelaphine Herpesvirus 1 malignant catarrhal fever virus in wildebeest placenta genetic variation of orf50 and a9 5 alleles
PLOS ONE, 2015Co-Authors: Dawn M. Grant, Felix Lankester, Ahmed Lugelo, Nicholas Mnyambwa, Ahab Ndabigaye, Julius Keyyu, R R Kazwala, Valerie Relf, David M HaigAbstract:Alcelaphine Herpesvirus–1 (AlHV-1), a causative agent of malignant catarrhal fever in cattle, was detected in wildebeest (Connochaetes taurinus) placenta tissue for the first time. Although viral load was low, the finding of viral DNA in over 50% of 94 samples tested lends support to the possibility that placental tissue could play a role in disease transmission and that wildebeest calves are infected in utero. Two viral loci were sequenced to examine variation among virus samples obtained from wildebeest and cattle: the ORF50 gene, encoding the lytic cycle transactivator protein, and the A9.5 gene, encoding a novel polymorphic viral glycoprotein. ORF50 was well conserved with six newly discovered alleles differing at only one or two base positions. In contrast, while only three new A9.5 alleles were discovered, these differed by up to 13% at the nucleotide level and up to 20% at the amino acid level. Structural homology searching performed with the additional A9.5 sequences determined in this study adds power to recent analysis identifying the four-helix bundle cytokine interleukin-4 (IL4) as the major homologue. The majority of MCF virus samples obtained from Tanzanian cattle and wildebeest encoded A9.5 polypeptides identical to the previously characterized A9.5 allele present in the laboratory maintained AlHV-1 C500 strain. This supports the view that AlHV-1 C500 is suitable for the development of a vaccine for wildebeest-associated MCF.
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Identification of immuno-reactive capsid proteins of malignant catarrhal fever viruses
Veterinary Microbiology, 2014Co-Authors: Kathryn Bartley, Neil F Inglis, Lisa Imrie, David Deane, Kevin Mclean, Erin D. T. Manson, Dawn M. Grant, A. Percival, David M HaigAbstract:Malignant catarrhal fever (MCF) is a fatal disease of cattle and other ungulates caused by certain gamma-Herpesviruses including Alcelaphine Herpesvirus-1 (AlHV-1) and ovine Herpesvirus-2 (OvHV-2). An attenuated virus vaccine based on AlHV-1 has been shown to induce virus-neutralising antibodies in plasma and nasal secretions of protected cattle but the targets of virus-specific antibodies are unknown. Proteomic analysis and western blotting of virus extracts allowed the identification of eight candidate AlHV-1 virion antigens. Recombinant expression of selected candidates and their OvHV-2 orthologues confirmed that two polypeptides, the products of the ORF17.5 and ORF65 genes, were antigens recognised by antibodies from natural MCF cases or from AlHV-1 vaccinated cattle. These proteins have potential as diagnostic and/or vaccine antigens.
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the a2 gene of Alcelaphine Herpesvirus 1 is a transcriptional regulator affecting cytotoxicity in virus infected t cells but is not required for malignant catarrhal fever induction in rabbits
Virus Research, 2014Co-Authors: Nevi Parameswaran, Benjamin G Dewals, Alain Vanderplasschen, Tom C Giles, Christopher D Deppmann, Martin J Blythe, Richard D Emes, David M HaigAbstract:Alcelaphine Herpesvirus-1 (AlHV-1) causes malignant catarrhal fever (MCF). The A2 gene of AlHV-1 is a member of the bZIP transcription factor family. We wished to determine whether A2 is a virulence gene or not and whether it is involved in pathogenesis by interference with host transcription pathways. An A2 gene knockout (A2ΔAlHV-1) virus, revertant (A2revAlHV-1) virus, and wild-type virus (wtAlHV-1) were used to infect three groups of rabbits. A2ΔAlHV-1-infected rabbits succumbed to MCF, albeit with a delayed onset compared to the control groups, so A2 is not a critical virulence factor. Differential gene transcription analysis by RNAseq and qRT-PCR validation of a selection of these was performed in infected large granular lymphocyte (LGL) T cells obtained in culture from the MCF-affected animals. A2 was involved in the transcriptional regulation of immunological, cell cycle and apoptosis pathways. In particular, there was a bias towards γδ T cell receptor (TCR) expression and downregulation of αβ TCR. TCR signalling, apoptosis, cell cycle, IFN-γ and NFAT pathways were affected. Of particular interest was partial inhibition of the cytotoxicity-associated pathways involving perforin and the granzymes A and B in the A2ΔAlHV-1-infected LGLs compared to controls. In functional assays, A2ΔAlHV-1-infected LGLs were significantly less cytotoxic than wtAlHV-1- and A2revAlHV-1-infected LGLs using rabbit corneal epithelial cells (SIRC) as targets. This implies that A2 is involved in a pathway enhancing the expression of LGL cytotoxicity. This is important as virus-infected T cell cytotoxicity in vivo has been suggested as a potential mechanism of disease induction in MCF.
Benjamin G Dewals - One of the best experts on this subject based on the ideXlab platform.
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Alcelaphine Herpesvirus 1 genes a7 and a8 regulate viral spread and are essential for malignant catarrhal fever
PLOS Pathogens, 2020Co-Authors: Francoise Myster, Alain Vanderplasschen, Nicolás M. Suárez, Andrew J. Davison, Meijiao Gong, Justine Javaux, Gavin S Wilkie, Timothy Connelley, Benjamin G DewalsAbstract:Alcelaphine Herpesvirus 1 (AlHV-1) is a gammaHerpesvirus that is carried asymptomatically by wildebeest. Upon cross-species transmission to other ruminants, including domestic cattle, AlHV-1 induces malignant catarrhal fever (MCF), which is a fatal lymphoproliferative disease resulting from proliferation and uncontrolled activation of latently infected CD8+ T cells. Two laboratory strains of AlHV-1 are used commonly in research: C500, which is pathogenic, and WC11, which has been attenuated by long-term maintenance in cell culture. The published genome sequence of a WC11 seed stock from a German laboratory revealed the deletion of two major regions. The sequence of a WC11 seed stock used in our laboratory also bears these deletions and, in addition, the duplication of an internal sequence in the terminal region. The larger of the two deletions has resulted in the absence of gene A7 and a large portion of gene A8. These genes are positional orthologs of the Epstein-Barr virus genes encoding envelope glycoproteins gp42 and gp350, respectively, which are involved in viral propagation and switching of cell tropism. To investigate the degree to which the absence of A7 and A8 participates in WC11 attenuation, recombinant viruses lacking these individual functions were generated in C500. Using bovine nasal turbinate and embryonic lung cell lines, increased cell-free viral propagation and impaired syncytia formation were observed in the absence of A7, whereas cell-free viral spread was inhibited in the absence of A8. Therefore, A7 appears to be involved in cell-to-cell viral spread, and A8 in viral cell-free propagation. Finally, infection of rabbits with either mutant did not induce the signs of MCF or the expansion of infected CD8+ T cells. These results demonstrate that A7 and A8 are both essential for regulating viral spread and suggest that AlHV-1 requires both genes to efficiently spread in vivo and reach CD8+ T lymphocytes and induce MCF.
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Genomic duplication and translocation of reactivation transactivator and bZIP-homolog genes is a conserved event in Alcelaphine Herpesvirus 1
Scientific Reports, 2016Co-Authors: Francoise Myster, Alain Vanderplasschen, Steven J. Van Beurden, Océane Sorel, Nicolás M. Suárez, Andrew J. Davison, Benjamin G DewalsAbstract:Alcelaphine Herpesvirus 1 (AlHV-1) is a gammaHerpesvirus carried asymptomatically by wildebeest. Upon cross-species transmission, AlHV-1 induces malignant catarrhal fever (MCF), a fatal lymphoproliferative disease of ruminants, including cattle. The strain C500 has been cloned as an infectious, pathogenic bacterial artificial chromosome (BAC) that is used to study MCF. Although AlHV-1 infection can be established in cell culture, multiple passages in vitro cause a loss of virulence associated with rearrangements of the viral genome. Here, sequencing of the BAC clone showed that the long unique region (LUR) of the genome is nearly identical to that of the previously sequenced strain from which the BAC was derived, and identified the duplication and translocation of a region from within LUR, containing the entire coding sequences of ORF50-encoding reactivation transactivator Rta and A6-encoding bZIP protein genes. The duplicated region was further located to a position within the terminal repeat (TR) and its deletion resulted in lower ORF50 expression levels and reduced viral fitness. Finally, the presence of a similar but not identical duplication and translocation containing both genes was found in AlHV-1 strain WC11. These results indicate that selection pressure for enhanced viral fitness may drive the duplication of ORF50 and A6 in AlHV-1.
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replacement of glycoprotein b in Alcelaphine Herpesvirus 1 by its ovine Herpesvirus 2 homolog implications in vaccine development for sheep associated malignant catarrhal fever
mSphere, 2016Co-Authors: Naomi S Taus, Hong Li, Benjamin G Dewals, Alain Vanderplasschen, Cristina W Cunha, Donald P KnowlesAbstract:ABSTRACT Vaccine development is a top priority in malignant catarrhal fever (MCF) research. In the case of sheep-associated MCF (SA-MCF) caused by ovine Herpesvirus 2 (OvHV-2), progress toward this objective has been hindered by the absence of methods to attenuate or modify the virus, since it cannot be propagated in vitro. As an alternative for vaccine development, in this study, we tested the hypothesis that one of the SA-MCF vaccine candidate targets, OvHV-2 glycoprotein B (gB), could be expressed by a nonpathogenic Alcelaphine Herpesvirus 1 (AlHV-1) and then evaluated the potential of the AlHV-1/OvHV-2 chimera to be used as a vaccine and a diagnostic tool. The construction and characterization of an AlHV-1/OvHV-2 chimeric virus that is nonpathogenic and expresses an OvHV-2 vaccine target are significant steps toward the development of an SA-MCF vaccine and also provide a valuable means to study OvHV-2 biology.
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small rna deep sequencing identifies viral micrornas during malignant catarrhal fever induced by Alcelaphine Herpesvirus 1
Journal of General Virology, 2015Co-Authors: Océane Sorel, Francoise Myster, Leonor Palmeira, Alain Vanderplasschen, Lee Tuddenham, Pierre Kerkhofs, Sebastien Pfeffer, Benjamin G DewalsAbstract:Alcelaphine Herpesvirus 1 (AlHV-1) is a γ-Herpesvirus (γ-HV) carried asymptomatically by wildebeest. Upon cross-species transmission, AlHV-1 induces a fatal lymphoproliferative disease named malignant catarrhal fever (MCF) in many ruminants, including cattle, and the rabbit model. Latency has been shown to be essential for MCF induction. However, the mechanisms causing the activation and proliferation of infected CD8+T cells are unknown. Many γ-HVs express microRNAs (miRNAs). These small non-coding RNAs can regulate expression of host or viral target genes involved in various pathways and are thought to facilitate viral infection and/or mediate activation and proliferation of infected lymphocytes. The AlHV-1 genome has been predicted to encode a large number of miRNAs. However, their precise contribution in viral infection and pathogenesis in vivo remains unknown. Here, using cloning and sequencing of small RNAs we identified 36 potential miRNAs expressed in a lymphoblastoid cell line propagated from a calf infected with AlHV-1 and developing MCF. Among the sequenced candidate miRNAs, 32 were expressed on the reverse strand of the genome in two main clusters. The expression of these 32 viral miRNAs was further validated using Northern blot and quantitative reverse transcription PCR in lymphoid organs of MCF-developing calves or rabbits. To determine the concerted contribution in MCF of 28 viral miRNAs clustered in the non-protein-coding region of the AlHV-1 genome, a recombinant virus was produced. The absence of these 28 miRNAs did not affect viral growth in vitro or MCF induction in rabbits, indicating that the AlHV-1 miRNAs clustered in this non-protein-coding genomic region are dispensable for MCF induction.
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Viral Semaphorin Inhibits Dendritic Cell Phagocytosis and Migration but Is Not Essential for GammaHerpesvirus-Induced Lymphoproliferation in Malignant Catarrhal Fever
Journal of Virology, 2015Co-Authors: Francoise Myster, Leonor Palmeira, Alain Vanderplasschen, Océane Sorel, Fabrice Bouillenne, Edwin Depauw, Isabelle Schwartz-cornil, Benjamin G DewalsAbstract:ABSTRACT Viral semaphorins are semaphorin 7A (sema7A) mimics found in pox- and Herpesviruses. Among Herpesviruses, semaphorins are encoded by gammaHerpesviruses of the Macavirus genus only. Alcelaphine Herpesvirus 1 (AlHV-1) is a macavirus that persistently infects wildebeest asymptomatically but induces malignant catarrhal fever (MCF) when transmitted to several species of susceptible ruminants and the rabbit model. MCF is caused by the activation/proliferation of latently infected T lymphocytes. Viral semaphorins have been suggested to mediate immune evasion mechanisms and/or directly alter host T cell function. We studied AlHV-sema, the viral semaphorin encoded by the A3 gene of AlHV-1. Phylogenetic analyses revealed independent acquisition of pox- and Herpesvirus semaphorins, suggesting that these proteins might have distinct functions. AlHV-sema showed a predicted three-dimensional structure very similar to sema7A and conserved key residues in sema7A-plexinC1 interaction. Expression analyses revealed that AlHV-sema is a secreted 93-kDa glycoprotein expressed during the early phase of virus replication. Purified AlHV-sema was able to bind to fibroblasts and dendritic cells and induce F-actin condensation and cell retraction through a plexinC1 and Rho/cofilin-dependent mechanism. Cytoskeleton rearrangement was further associated with inhibition of phagocytosis by dendritic cells and migration to the draining lymph node. Next, we generated recombinant viruses and demonstrated that the lack of A3 did not significantly affect virus growth in vitro and did not impair MCF induction and associated lymphoproliferative lesions. In conclusion, AlHV-sema has immune evasion functions through mechanisms similar to poxvirus semaphorin but is not directly involved in host T cell activation during MCF. IMPORTANCE Whereas most poxviruses encode viral semaphorins, semaphorin-like genes have only been identified in few gammaHerpesviruses belonging to the Macavirus genus. Alcelaphine Herpesvirus 1 (AlHV-1) is a macavirus carried asymptomatically by wildebeest but induces a latency-associated lymphoproliferative disease of T lymphocytes in various ruminant species, namely, malignant catarrhal fever (MCF). Viral semaphorins have been hypothesized to have immune evasion functions and/or be involved in activating latently infected T cells. We present evidence that the viral semaphorin AlHV-sema inhibits dendritic cell phagocytosis and migration to the draining lymph node, both being indispensable mechanisms for protective antiviral responses. Next, we engineered recombinant viruses unable to express AlHV-sema and demonstrated that this protein is dispensable for the induction of MCF. In conclusion, this study suggests that Herpesvirus and poxvirus semaphorins have independently evolved similar functions to thwart the immune system of the host while AlHV-sema is not directly involved in MCF-associated T-cell activation.
Alain Vanderplasschen - One of the best experts on this subject based on the ideXlab platform.
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Alcelaphine Herpesvirus 1 genes a7 and a8 regulate viral spread and are essential for malignant catarrhal fever
PLOS Pathogens, 2020Co-Authors: Francoise Myster, Alain Vanderplasschen, Nicolás M. Suárez, Andrew J. Davison, Meijiao Gong, Justine Javaux, Gavin S Wilkie, Timothy Connelley, Benjamin G DewalsAbstract:Alcelaphine Herpesvirus 1 (AlHV-1) is a gammaHerpesvirus that is carried asymptomatically by wildebeest. Upon cross-species transmission to other ruminants, including domestic cattle, AlHV-1 induces malignant catarrhal fever (MCF), which is a fatal lymphoproliferative disease resulting from proliferation and uncontrolled activation of latently infected CD8+ T cells. Two laboratory strains of AlHV-1 are used commonly in research: C500, which is pathogenic, and WC11, which has been attenuated by long-term maintenance in cell culture. The published genome sequence of a WC11 seed stock from a German laboratory revealed the deletion of two major regions. The sequence of a WC11 seed stock used in our laboratory also bears these deletions and, in addition, the duplication of an internal sequence in the terminal region. The larger of the two deletions has resulted in the absence of gene A7 and a large portion of gene A8. These genes are positional orthologs of the Epstein-Barr virus genes encoding envelope glycoproteins gp42 and gp350, respectively, which are involved in viral propagation and switching of cell tropism. To investigate the degree to which the absence of A7 and A8 participates in WC11 attenuation, recombinant viruses lacking these individual functions were generated in C500. Using bovine nasal turbinate and embryonic lung cell lines, increased cell-free viral propagation and impaired syncytia formation were observed in the absence of A7, whereas cell-free viral spread was inhibited in the absence of A8. Therefore, A7 appears to be involved in cell-to-cell viral spread, and A8 in viral cell-free propagation. Finally, infection of rabbits with either mutant did not induce the signs of MCF or the expansion of infected CD8+ T cells. These results demonstrate that A7 and A8 are both essential for regulating viral spread and suggest that AlHV-1 requires both genes to efficiently spread in vivo and reach CD8+ T lymphocytes and induce MCF.
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Genomic duplication and translocation of reactivation transactivator and bZIP-homolog genes is a conserved event in Alcelaphine Herpesvirus 1
Scientific Reports, 2016Co-Authors: Francoise Myster, Alain Vanderplasschen, Steven J. Van Beurden, Océane Sorel, Nicolás M. Suárez, Andrew J. Davison, Benjamin G DewalsAbstract:Alcelaphine Herpesvirus 1 (AlHV-1) is a gammaHerpesvirus carried asymptomatically by wildebeest. Upon cross-species transmission, AlHV-1 induces malignant catarrhal fever (MCF), a fatal lymphoproliferative disease of ruminants, including cattle. The strain C500 has been cloned as an infectious, pathogenic bacterial artificial chromosome (BAC) that is used to study MCF. Although AlHV-1 infection can be established in cell culture, multiple passages in vitro cause a loss of virulence associated with rearrangements of the viral genome. Here, sequencing of the BAC clone showed that the long unique region (LUR) of the genome is nearly identical to that of the previously sequenced strain from which the BAC was derived, and identified the duplication and translocation of a region from within LUR, containing the entire coding sequences of ORF50-encoding reactivation transactivator Rta and A6-encoding bZIP protein genes. The duplicated region was further located to a position within the terminal repeat (TR) and its deletion resulted in lower ORF50 expression levels and reduced viral fitness. Finally, the presence of a similar but not identical duplication and translocation containing both genes was found in AlHV-1 strain WC11. These results indicate that selection pressure for enhanced viral fitness may drive the duplication of ORF50 and A6 in AlHV-1.
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replacement of glycoprotein b in Alcelaphine Herpesvirus 1 by its ovine Herpesvirus 2 homolog implications in vaccine development for sheep associated malignant catarrhal fever
mSphere, 2016Co-Authors: Naomi S Taus, Hong Li, Benjamin G Dewals, Alain Vanderplasschen, Cristina W Cunha, Donald P KnowlesAbstract:ABSTRACT Vaccine development is a top priority in malignant catarrhal fever (MCF) research. In the case of sheep-associated MCF (SA-MCF) caused by ovine Herpesvirus 2 (OvHV-2), progress toward this objective has been hindered by the absence of methods to attenuate or modify the virus, since it cannot be propagated in vitro. As an alternative for vaccine development, in this study, we tested the hypothesis that one of the SA-MCF vaccine candidate targets, OvHV-2 glycoprotein B (gB), could be expressed by a nonpathogenic Alcelaphine Herpesvirus 1 (AlHV-1) and then evaluated the potential of the AlHV-1/OvHV-2 chimera to be used as a vaccine and a diagnostic tool. The construction and characterization of an AlHV-1/OvHV-2 chimeric virus that is nonpathogenic and expresses an OvHV-2 vaccine target are significant steps toward the development of an SA-MCF vaccine and also provide a valuable means to study OvHV-2 biology.
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small rna deep sequencing identifies viral micrornas during malignant catarrhal fever induced by Alcelaphine Herpesvirus 1
Journal of General Virology, 2015Co-Authors: Océane Sorel, Francoise Myster, Leonor Palmeira, Alain Vanderplasschen, Lee Tuddenham, Pierre Kerkhofs, Sebastien Pfeffer, Benjamin G DewalsAbstract:Alcelaphine Herpesvirus 1 (AlHV-1) is a γ-Herpesvirus (γ-HV) carried asymptomatically by wildebeest. Upon cross-species transmission, AlHV-1 induces a fatal lymphoproliferative disease named malignant catarrhal fever (MCF) in many ruminants, including cattle, and the rabbit model. Latency has been shown to be essential for MCF induction. However, the mechanisms causing the activation and proliferation of infected CD8+T cells are unknown. Many γ-HVs express microRNAs (miRNAs). These small non-coding RNAs can regulate expression of host or viral target genes involved in various pathways and are thought to facilitate viral infection and/or mediate activation and proliferation of infected lymphocytes. The AlHV-1 genome has been predicted to encode a large number of miRNAs. However, their precise contribution in viral infection and pathogenesis in vivo remains unknown. Here, using cloning and sequencing of small RNAs we identified 36 potential miRNAs expressed in a lymphoblastoid cell line propagated from a calf infected with AlHV-1 and developing MCF. Among the sequenced candidate miRNAs, 32 were expressed on the reverse strand of the genome in two main clusters. The expression of these 32 viral miRNAs was further validated using Northern blot and quantitative reverse transcription PCR in lymphoid organs of MCF-developing calves or rabbits. To determine the concerted contribution in MCF of 28 viral miRNAs clustered in the non-protein-coding region of the AlHV-1 genome, a recombinant virus was produced. The absence of these 28 miRNAs did not affect viral growth in vitro or MCF induction in rabbits, indicating that the AlHV-1 miRNAs clustered in this non-protein-coding genomic region are dispensable for MCF induction.
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Viral Semaphorin Inhibits Dendritic Cell Phagocytosis and Migration but Is Not Essential for GammaHerpesvirus-Induced Lymphoproliferation in Malignant Catarrhal Fever
Journal of Virology, 2015Co-Authors: Francoise Myster, Leonor Palmeira, Alain Vanderplasschen, Océane Sorel, Fabrice Bouillenne, Edwin Depauw, Isabelle Schwartz-cornil, Benjamin G DewalsAbstract:ABSTRACT Viral semaphorins are semaphorin 7A (sema7A) mimics found in pox- and Herpesviruses. Among Herpesviruses, semaphorins are encoded by gammaHerpesviruses of the Macavirus genus only. Alcelaphine Herpesvirus 1 (AlHV-1) is a macavirus that persistently infects wildebeest asymptomatically but induces malignant catarrhal fever (MCF) when transmitted to several species of susceptible ruminants and the rabbit model. MCF is caused by the activation/proliferation of latently infected T lymphocytes. Viral semaphorins have been suggested to mediate immune evasion mechanisms and/or directly alter host T cell function. We studied AlHV-sema, the viral semaphorin encoded by the A3 gene of AlHV-1. Phylogenetic analyses revealed independent acquisition of pox- and Herpesvirus semaphorins, suggesting that these proteins might have distinct functions. AlHV-sema showed a predicted three-dimensional structure very similar to sema7A and conserved key residues in sema7A-plexinC1 interaction. Expression analyses revealed that AlHV-sema is a secreted 93-kDa glycoprotein expressed during the early phase of virus replication. Purified AlHV-sema was able to bind to fibroblasts and dendritic cells and induce F-actin condensation and cell retraction through a plexinC1 and Rho/cofilin-dependent mechanism. Cytoskeleton rearrangement was further associated with inhibition of phagocytosis by dendritic cells and migration to the draining lymph node. Next, we generated recombinant viruses and demonstrated that the lack of A3 did not significantly affect virus growth in vitro and did not impair MCF induction and associated lymphoproliferative lesions. In conclusion, AlHV-sema has immune evasion functions through mechanisms similar to poxvirus semaphorin but is not directly involved in host T cell activation during MCF. IMPORTANCE Whereas most poxviruses encode viral semaphorins, semaphorin-like genes have only been identified in few gammaHerpesviruses belonging to the Macavirus genus. Alcelaphine Herpesvirus 1 (AlHV-1) is a macavirus carried asymptomatically by wildebeest but induces a latency-associated lymphoproliferative disease of T lymphocytes in various ruminant species, namely, malignant catarrhal fever (MCF). Viral semaphorins have been hypothesized to have immune evasion functions and/or be involved in activating latently infected T cells. We present evidence that the viral semaphorin AlHV-sema inhibits dendritic cell phagocytosis and migration to the draining lymph node, both being indispensable mechanisms for protective antiviral responses. Next, we engineered recombinant viruses unable to express AlHV-sema and demonstrated that this protein is dispensable for the induction of MCF. In conclusion, this study suggests that Herpesvirus and poxvirus semaphorins have independently evolved similar functions to thwart the immune system of the host while AlHV-sema is not directly involved in MCF-associated T-cell activation.
H W Reid - One of the best experts on this subject based on the ideXlab platform.
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genome re arrangements associated with loss of pathogenicity of the γ Herpesvirus Alcelaphine Herpesvirus 1
Research in Veterinary Science, 2003Co-Authors: H Wright, James P Stewart, R G Ireri, I Campbell, H W Reid, David M HaigAbstract:The Alcelaphine Herpesvirus 1 (AlHV-1) causes malignant catarrhal fever in ruminants. Previous work had shown that serial passage of AlHV-1 in culture resulted in genome alterations that are associated with a loss in pathogenicity. Here we have analysed the re-arrangements that occur in more detail. None of the observed re-arrangements was entirely consistent. However, they did all involve translocation of a similar region of DNA from around the centre of the genome to areas either next to or in between terminal repeat elements at either end of the genome. There was also a concomitant loss of the wild-type locus. These re-arrangements appeared to be associated with the loss of virulence and the appearance of cell-free virus.
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Malignant catarrhal fever caused by ovine Herpesvirus-2 in pigs in Norway
Veterinary Record, 1998Co-Authors: T. Løken, M. Aleksandersen, H W ReidAbstract:This paper describes the first cases of malignant catarrhal fever (MCF) in pigs in which the diagnosis was verified aetiologically by polymerase chain reaction (PCR) and DNA analysis and by the demonstration of antibodies. Three pigs on two separate premises showed clinical signs, gross pathological and histopathological lesions which were in many respects similar to those of MCF in ruminants. The pigs were housed adjacent to sheep and DNA of ovine Herpesvirus-2 (OHV-2) was detected by PCR in tissues of all the pigs. In addition, antibody to Alcelaphine Herpesvirus-1 was detected in the serum of the pigs and in five in-contact sheep. It is concluded that the disease described is MCF of pigs caused by OHV-2.
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Characterisation of the lymphoproliferation in rabbits experimentally affected with malignant catarrhal fever
Veterinary Microbiology, 1996Co-Authors: A. Schock, H W ReidAbstract:Abstract Malignant catarrhal fever (MCF) in rabbits caused by the three Herpesviruses: Alcelaphine Herpesvirus-1 (AHV-1), ovine Herpesvirus-2 (OHV-2) and hippotragine Herpesvirus-1 (HipHV-1) induced hyperplasia of lymphoid tissues and accumulations of mononuclear lymphoid cells in non-lymphoid tissues. However, certain lymph nodes were affected preferentially. The lymphoid cells in non-lymphoid tissues were CD43 + T-cells which showed evidence of in situ multiplication. A more detailed phenotypic analysis of splenocytes and lymph node cells in AHV-1 infected rabbits suggested that the hyperplasia was probably due to the expansion of CD8 + T-cells. On the basis of these data and the observations of other authors, that no or very little viral expression can be detected in lesions of MCF affected animals, we propose that the pathogenesis of MCF results from a dysregulation of a secretory T-cell activator. The variable pathology induced by the three viruses may reflect a quantitative or qualitative difference in this proposed activator.
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identification of a region of the Alcelaphine Herpesvirus 1 genome associated with virulence for rabbits
Veterinary Microbiology, 1995Co-Authors: J A Handley, D R Sargan, A J Herring, H W ReidAbstract:Abstract The gammaHerpesvirus Alcelaphine Herpesvirus 1 (AHV-1) causes the fatal lymphoproliferative disease known as malignant catarrhal fever (MCF), in susceptible hosts. The virulent C500 isolate of AHV-1 became attenuated for the laboratory model, the rabbit, as a result of serial passage in cells of bovine origin. This work describes the identification of a region of the central unique sequence of the C500 genome, located close to the terminal repeat units of the molecule, which is altered on attenuation. The virulent C500 genome contains two copies of a sequence of approximately 2 kbp, contained within a 7 kbp region of the unique DNA located adjacent to the terminal repeats at the left end of the molecule. In the genome of the attenuated virus, there are also two copies of the 2 kbp sequence but they are located at the ends of the attenuated genome unique region, adjacent to the terminally repeated sequences. One open reading frame (ORF), designated putative polypeptide 5, was altered on attentuation such that the 3′ sequence was lost. The location of this ORF, coupled with the loss of its 3′ sequence, suggests that this ORF may encode a gene involved in the virulent mechanisms of this virus, in a manner similar to that of the transforming proteins of Herpesvirus saimiri (HSV).
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PCR detection of ovine Herpesvirus-2 DNA in Indonesian ruminants — normal sheep and clinical cases of malignant catarrhal fever
Veterinary Microbiology, 1994Co-Authors: A. Wiyono, S. I. F. Baxter, M. Saepulloh, R. Damayanti, P. Daniels, H W ReidAbstract:Malignant catarrhal fever (MCF), a fatal viral disease of cattle and other large ruminants, has a worldwide distribution. There are two forms of the disease, one of which, is caused by Alcelaphine Herpesvirus-1 (AHV-1) and is derived from wildebeest. The other form is associated with domestic sheep and is caused by ovine Herpesvirus-2 (OHV-2). The disease in Indonesia is sheep-associated with the preferred livestock of this area, Balinese cattle (Bos javanicus) and water buffalo (Bubalus bubalis), both highly susceptible to SA-MCF. The incidence in these species is thought to be high but the prevalence and economic losses attributable to SA-MCF have been difficult to assess. A polymerase chain reaction (PCR) test, based on a cloned OHV-2 gene sequence, was successfully applied to the detection of OHV-2 DNA in normal sheep and animals affected with SA-MCF. OHV-2 DNA was detected in eleven confirmed cases of SA-MCF and in the peripheral blood leucocyte (PBL) fraction of six latently infected sheep. These findings have confirmed that the PCR can be of value in establishing a diagnosis of MCF and that the aetiological agent of MCF in Indonesia is OHV-2. The amplification of DNA from the PBL of goats suggests that they are infected with a similar or identical Herpesvirus.
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A field vaccine trial in Tanzania demonstrates partial protection against Malignant Catarrhal Fever in cattle
Tanzania Veterinary Journal, 2020Co-Authors: Felix Lankester, George C Russell, Dawn M. Grant, Ahmed Lugelo, Nicholas Mnyambwa, Julius Keyyu, A. Ndabigaye, Rudovick R. Kazwala, A. Percival, David DeaneAbstract:Malignant Catarrhal Fever (MCF) is a fatal lymphoproliferative disease of cattle that, in East Africa, follows contact with wildebeest carrying the causative virus Alcelaphine Herpesvirus 1 (AlHV-1). A vaccine field trial involving an attenuated AlHV-1 virus vaccine was performed over two wildebeest calving seasons on the Simanjiro Plain of northern Tanzania. Each of the two phases of the field trial consisted ofgroups of 50 vaccinated and unvaccinated cattle, which were subsequently exposed to AlHV-1 challenge by herding towards wildebeest. Vaccination resulted in the induction of virus-specific and virus-neutralizing antibodies, whilst some cattle in the unvaccinated groups also developed virus-specific antibody responses but only after the start of the challenge phase of the trial. PCR of DNA from blood samples detected AlHV-1 infection in both groups of cattle but the frequency of infection was significantly lower in the vaccinated groups. Some infected animals showed clinical signs suggestive of MCF but few animals went on to develop fatal MCF, with similar numbers in vaccinated and unvaccinated groups.This study demonstrated a baseline level of MCF-seropositivity among cattle in northern Tanzania of 1% and showed that AlHV-1 virus-neutralizing antibodies could be induced in Tanzanian zebu shorthorn cross cattle by our attenuated vaccine, a correlate of protection in previous experimental trials. The vaccine reduced infection rates by 56% in cattle exposed to wildebeest but protection from fatal MCF could not be determined due to the low number of fatal cases. Keywords: Alcelaphine Herpesvirus 1, malignant catarrhal fever, vaccine field trial, vaccine efficacy, wildebeest
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A randomised vaccine field trial in Kenya demonstrates protection against wildebeest-associated malignant catarrhal fever in cattle.
Vaccine, 2019Co-Authors: Elizabeth A. J. Cook, George C Russell, Dawn M. Grant, Felix Lankester, Christine N. Mutisya, Lazarus Omoto, Elizabeth Dobson, Vishvanath NeneAbstract:Abstract Wildebeest-associated malignant catarrhal fever (WA-MCF), a fatal disease of cattle caused by Alcelaphine Herpesvirus 1 (AlHV-1), is one of the most important seasonal diseases of cattle in wildebeest endemic areas, with annual incidence reaching 10%. Here we report efficacy of over 80% for a vaccine based on the attenuated AlHV-1 C500 strain, in preventing fatal WA-MCF in cattle exposed to natural wildebeest challenge. The study was conducted at Kapiti Plains Ranch Ltd, south-east of Nairobi, Kenya. In 2016, 146 cattle were selected for a randomised placebo-controlled trial. Cattle were stratified according to breed and age and randomly assigned to groups given vaccine or culture medium mixed with Emulsigen®. Cattle received prime and boost inoculations one month apart and few adverse reactions (n = 4) were observed. Indirect ELISA demonstrated that all cattle in the vaccine group developed a serological response to AlHV-1. The study herd was grazed with wildebeest from one month after booster vaccination. Three cattle, two that received vaccine and one control, succumbed to conditions unrelated to WA-MCF before the study ended. Twenty-five cattle succumbed to WA-MCF; four of the remaining 71 cattle in the vaccine group (5.6%) and 21 of the remaining 72 control cattle (29.2%; χ2 = 13.6, df = 1, p
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A field vaccine trial in Tanzania demonstrates partial protection against malignant catarrhal fever in cattle
Vaccine, 2015Co-Authors: Felix Lankester, George C Russell, Dawn M. Grant, Ahmed Lugelo, Nicholas Mnyambwa, Julius Keyyu, A. Ndabigaye, Rudovick R. Kazwala, A. Percival, David DeaneAbstract:Malignant catarrhal fever (MCF) is a fatal lymphoproliferative disease of cattle that, in East Africa, results from transmission of the causative virus, Alcelaphine Herpesvirus 1 (AlHV-1), from wildebeest. A vaccine field trial involving an attenuated AlHV-1 virus vaccine was performed over two wildebeest calving seasons on the Simanjiro Plain of northern Tanzania. Each of the two phases of the field trial consisted of groups of 50 vaccinated and unvaccinated cattle, which were subsequently exposed to AlHV-1 challenge by herding toward wildebeest. Vaccination resulted in the induction of virus-specific and virus-neutralizing antibodies. Some cattle in the unvaccinated groups also developed virus-specific antibody responses but only after the start of the challenge phase of the trial. PCR of DNA from blood samples detected AlHV-1 infection in both groups of cattle but the frequency of infection was significantly lower in the vaccinated groups. Some infected animals showed clinical signs suggestive of MCF but few animals went on to develop fatal MCF, with similar numbers in vaccinated and unvaccinated groups. This study demonstrated a baseline level of MCF-seropositivity among cattle in northern Tanzania of 1% and showed that AlHV-1 virus-neutralizing antibodies could be induced in Tanzanian zebu shorthorn cross cattle by our attenuated vaccine, a correlate of protection in previous experimental trials. The vaccine reduced infection rates by 56% in cattle exposed to wildebeest but protection from fatal MCF could not be determined due to the low number of fatal cases.
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The effect of the TLR9 ligand CpG-oligodeoxynucleotide on the protective immune response to Alcelaphine Herpesvirus-1-mediated malignant catarrhal fever in cattle
Veterinary Research, 2014Co-Authors: Nevi Parameswaran, George C Russell, Helen Todd, David Deane, Dawn M. Grant, Mark P Dagleish, Kathryn Bartley, David M HaigAbstract:We wished to determine the effect of of CpG ODN adjuvant on the magnitude and duration of protective immunity against Alcelaphine Herpesvirus-1 (AlHV-1) malignant catarrhal fever (MCF), a fatal lymphoproliferative disease of cattle. Immunity was associated with a mucosal barrier of virus-neutralising antibody. The results showed that CpG ODN included either with emulsigen adjuvant and attenuated AlHV-1 (atAlHV-1) or alone with atAlHV-1 did not affect the overall protection from clinical disease or duration of immunity achieved using emulsigen and atAlHV-1. This is in contrast to other similar studies in cattle with BoHV-1 or cattle and pigs with various other immunogens. In addition to this, several other novel observations were made, not reported previously. Firstly, we were able to statistically verify that vaccine protection against MCF was associated with virus-neutralising antibodies (nAbs) in nasal secretions but was not associated with antibodies in blood plasma, nor with total virus-specific antibody (tAb) titres in either nasal secretions or blood plasma. Furthermore, CpG ODN alone as adjuvant did not support the generation of virus-neutralising antibodies. Secondly, there was a significant boost in tAb in animals with MCF comparing titres before and after challenge. This was not seen with protected animals. Finally, there was a strong IFN-γ response in animals with emulsigen and atAlHV-1 immunisation, as measured by IFN-γ secreting PBMC in culture (and a lack of IL-4) that was not affected by the inclusion of CpG ODN. This suggests that nAbs at the oro-nasal-pharyngeal region are important in protection against AlHV-1 MCF.
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a novel spliced gene in Alcelaphine Herpesvirus 1 encodes a glycoprotein which is secreted in vitro
Journal of General Virology, 2013Co-Authors: George C Russell, David M Haig, Helen Todd, David Deane, Ann Percival, Mark P Dagleish, James P StewartAbstract:Herpesviruses often contain cryptic, spliced genes that are not obvious from the initial in silico annotation. Alcelaphine Herpesvirus 1 (AlHV-1) contains 72 annotated ORFs but there are also a number of gaps between these that may have protein-coding potential. Comparative analysis of coding potential between AlHV-1 and the related ovine Herpesvirus 2 (OvHV-2) revealed a putative novel spliced gene that we have termed A9.5. Analysis of cDNA clones from AlHV-1-infected cells revealed three overlapping clones corresponding to A9.5 and the coding sequence was confirmed by reverse transcription PCR of RNA from AlHV-1-infected cattle tissues. The A9.5 gene was predicted to encode a secreted glycoprotein with molecular mass 19 kDa. Empirical analysis showed that a recombinant haemagglutinin-tagged A9.5 fusion protein was secreted from transfected cells and had a molecular mass of 45 kDa, which was reduced to 20 kDa by endoglycosidase F treatment, confirming that A9.5 was a secreted glycoprotein. In situ RNA hybridization showed that A9.5 was expressed in cells associated with malignant catarrhal fever (MCF) lesions in infected cattle. Detailed analysis of the available OvHV-2 sequences revealed an homologous gene (Ov9.5) with conserved splicing signals and predicted amino acid sequence features in both sequenced isolates of this related virus. We have therefore identified a novel spliced gene in two related macaviruses that is expressed in MCF lesions. Future work will determine its importance for the pathogenesis of disease.
