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N J Watt - One of the best experts on this subject based on the ideXlab platform.
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phenotypic analysis of lymphocyte populations in the lungs and regional lymphoid tissue of sheep naturally infected with maedi visna virus
Clinical and Experimental Immunology, 2008Co-Authors: N J Watt, David R Sargan, David Collie, Neil Macintyre, Ian McconnellAbstract:We have analysed the phenotype of lymphocytes in lung and regional lymph node of symptomatic and asymptomatic sheep infected with the Ovine Lentivirus, maedi visna virus (MVV). Compared to equivalent tissues from age-matched, non-infected controls, MVV-infected sheep show increased numbers of lymphocytes in the lung, both in the bronchus-associated lymphoid tissue (BALT) and in the alveolar septae. Both CD8+ and CD4+ T lymphocyte numbers in alveolar septae were increased, particularly in animals with clinical respiratory disease. The ratio of CD8+ to CD4+ lymphocytes was similar to that in normal lung. In both MVV-infected and uninfected animals a high proportion of pulmonary lymphocytes, particularly in the alveolar septae, did not express the CD5 antigen, suggesting that they were activated. The number of activated cells was higher in infected sheep. Variable numbers of alveolar macrophages containing MVV-core protein were present in alveolar lumina, the majority of positive cells showing morphological evidence of activation. In regional lymphoid tissue there were increased numbers of CD8+ and gamma delta expressing T cells in lymphoid follicles and germinal centres of infected animals. The specificity of these cells is unknown and we could find no evidence for the presence of cells productively infected with the virus in these structures. This study shows that activated T lymphocytes, particularly of the CD8 subset, play a major part in the pathogenesis of MVV-induced pulmonary and regional lymph node lesions.
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a new sensitive serological assay for detection of Lentivirus infections in small ruminants
Clinical and Vaccine Immunology, 1999Co-Authors: Eric Saman, Geertrui Van Eynde, Belén Extramiana, Francesco Tolari, Lorenzo Gonzalez, N J Watt, Gordon D. Harkiss, Beatriz Amorena, L Lujan, Juan Jose BadiolaAbstract:Lentivirus infections in small ruminants represent an economic problem affecting several European countries with important sheep-breeding industries. Programs for control and eradication of these infections are being initiated and require reliable screening assays. This communication describes the construction and evaluation of a new serological screening enzyme-linked immunosorbent assay (ELISA) for the detection of antibodies to maedi-visna virus (MVV) in sheep and to caprine arthritis encephalitis virus (CAEV) in goats. The solid phase is sensitized with a combination of the major core protein p25 of MVV produced in Escherichia coli and a peptide derived from the immunodominant region of the viral transmembrane protein gp46. The peptide carries an N-terminal biotin residue and is complexed with streptavidin prior to being coated. The new assay was evaluated with 2,336 sheep serum samples from different European countries with large differences in the levels of prevalence of MVV infections, and the results have been compared to those of the standard agar gel immunodiffusion test. Discrepant samples were analyzed by Western blotting with viral lysate, and most sera could be classified unambiguously. The estimated overall sensitivity of the new ELISA was 99.4% (95% confidence interval [CI], 98.4 to 99.8%) and the specificity was 99.3% (95% CI, 98.7 to 99.6%). A limited set of goat sera (n 5 212) was also analyzed, with similar results. These data indicate that the new assay is a reliable tool that can be used in control and eradication programs for small ruminant Lentivirus infections. Maedi-visna virus (MVV, also termed Ovine Lentivirus) is a nononcogenic, exogenous retrovirus belonging to the Lentiviridae subfamily and related to human immunodeficiency virus (5, 18, 20). MVV infection in sheep is characterized by a relatively long asymptomatic period in which the virus persists in the presence of a strong humoral and cellular response. Following a variable incubation period (2 to 10 years), the virus may cause a chronic, progressive, inflammatory disease in the lungs, joints, and mammary glands of infected animals. In the central nervous system, inflammation and degenerative processes can result from an MVV infection (2). Caprine arthritis-encephalitis virus (CAEV) is genetically and antigenically closely related to MVV (20). CAEV infection in goats is widespread and may cause important economic losses. The main clinical symptoms are arthritis, chronic subclinical mastitis, and interstitial pneumonia. Encephalitis is often diagnosed in young goats and in adult animals, and encephalitis is seen more frequently than the arthritis observed in MVV-infected sheep. MVV-infected sheep produce high titers of serum antibodies against viral capsid and envelope proteins. Several serological diagnostic tests to detect these antibodies have been described (6, 7, 9, 11, 17, 21), but only two methods, the agar gel immunodiffusion test (AGIDT) and the whole-virus enzymelinked immunosorbent assay (WV-ELISA) are used routinely
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immunohistological study of the depressed cutaneous dth response in sheep naturally infected with an Ovine Lentivirus maedi visna virus
Clinical and Experimental Immunology, 1996Co-Authors: I T G Pyrah, N J WattAbstract:The gross and immunohistological characteristics of the purified protein derivative (PPD)-induced cutaneous DTH reaction were studied in a group of sheep naturally infected with Maedi-Visna virus (MVV), and compared with reactions obtained in a matched control group. There was a marked, but variable, depression in the DTH lesion in the MVV group associated with a decreased density of polymorphonuclear neutrophils (PMN) and CD4+ cells in the early reaction. There were no significant differences in the densities of CD8+, γ/δ T cells, macrophages, B cells and MHC class II-expressing cells. This work indicates that there is a significant alteration in the initial trafficking of PMN and CD4+ cells into a DTH response area in sheep infected with MVV.
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distribution and quantitation of lung parenchymal contractile tissue in Ovine Lentivirus induced lymphoid interstitial pneumonia do tissue forces limit lung distensibility
Laboratory Investigation, 1995Co-Authors: D D S Collie, I Pyrah, N J WattAbstract:BACKGROUND : Lymphoid interstitial pneumonia (LIP) is frequently identified in sheep infected with the Ovine Lentivirus, maedi-visna virus (MVV). Functional consequences of this condition include a reduction in lung distensibility that cannot be explained by the density of surface forces within the lung parenchyma. A potential source of tissue forces to account for this functional deficit is the substantial parenchymal smooth muscle hyperplasia that is a feature of the lung pathology. This investigation examines the relationship between lung distensibility and the quantity and distribution of smooth muscle hyperplasia in MVV-induced LIP. EXPERIMENTAL DESIGN : Immunohistochemical localization of α-smooth muscle actin (ASMA) was used to identify parenchymal contractile tissue. The distribution and morphometric quantitation of ASMA in lung parenchyma was determined in normal sheep lungs and in lungs from sheep seropositive for MVV. The relationship between the volume density of ASMA in lung parenchyma (Vv'ASMA') and static lung compliance (Cst) and lung distensibility (K) was examined. RESULTS : In normal lungs, ASMA was expressed by typical smooth muscle cells surrounding airways and blood vessels, by cells at the alveolar septal tips protruding into the alveolar ducts, and, rarely, by individual cells within septa. In MVV-seropositive sheep with minimal histopathology, increased ASMA expression occurred in association with early interstitial infiltrates and was located both at septal tips and within septa. With more severe pathology, ASMA-expressing cells became organized into bundles within obviously thickened septa and septal tips. In maedi, Vv'ASMA' is negatively correlated with K and Cst (r s = -0.614 ; p < 0.005 ; and r s = -0.504 ; p < 0.025, respectively). However, partial correlation coefficients indicate that Vv'ASMA' and lung parenchymal tissue density (Vvt) are strongly interdependent. CONCLUSIONS : ASMA expression in normal sheep lung parenchyma follows a similar pattern of distribution to that described for human lungs. The quantity of ASMA in lung parenchyma in LIP associated with MVV infection is negatively correlated with lung distensibility ; however, whether this is a causal association remains undetermined.
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Ovine Lentivirus maedi visna virus protein expression in sheep alveolar macrophages
Veterinary Pathology, 1994Co-Authors: L Lujan, David Collie, I Begara, N J WattAbstract:The expression of gag (p15, p25) and env gene products in Ovine Lentivirus-infected cells was studied in 20 adult Texel ewes seropositive to maedi-visna virus and 10 seronegative matched controls. Bronchoalveolar lavage was performed to recover alveolar cell pools from which cytocentrifuge preparations were made. Single and double immunocytochemical techniques were applied to study viral replication and coexpression of viral markers with markers for macrophages, lymphocytes, and major histocompatibility complex (MHC) class II. Aveolar macrophages of eight of 20 infected sheep (40%) were positive for viral protein expression. The percentage of positive macrophages varied from < 1% to 12% of the total population of macrophages. Viral protein expression was not detected in lymphocytes or other cell types. A relationship between virus-replicating macrophages and differential expression of MHC class II molecules, upregulated in Ovine Lentivirus infection, could not be established. Pathology was evaluated in nine infected ewes. Animals with the highest levels of positive cells had moderate or severe lymphoid interstitial pneumonia. However, sheep with similar degrees of lesions had lower percentages of positive macrophages or were negative for viral protein detection. These results support the idea that a partial or even a complete loss in the restriction mechanism of maedi-visna virus in lungs can occur in some individuals.
Opendra Narayan - One of the best experts on this subject based on the ideXlab platform.
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Downloaded from www.microbiologyresearch.org by
2016Co-Authors: Dinesh K. Singh, Yahia Chebloune, Leila Mselli-lakhal, Bradley M. Karr, Opendra NarayanAbstract:Ovine Lentivirus-infected macrophages mediate productive infection in cell types that are not susceptible to infection with cell-free viru
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genetic characterization of two phenotypically distinct north american Ovine Lentiviruses and their possible origin from caprine arthritis encephalitis virus
Virology, 1996Co-Authors: Bradley M. Karr, Yahia Chebloune, Kevin Leung, Opendra NarayanAbstract:Ovine and caprine Lentiviruses are closely related genetically and antigenically although the diseases that these viruses cause in their respective host animals can vary greatly. In sheep, syndromes consist primarily of interstitial pneumonia with rare occurrences of arthritis and encephalitis, whereas in goats, the disease expresses mainly as arthritis in adult animals with rare cases of encephalitis in newborns. Experimentally, viruses from either sheep or goats can infect animals of the reciprocal species and many field strains of Ovine Lentivirus have biological properties similar to those of caprine viruses. However, a molecular correlation for the phenotypic differences between Ovine and caprine Lentivirus strains is unknown. To investigate this, we examined genetic characteristics of two phenotypically distinct North American Ovine Lentiviruses. Nucleotide sequence analysis of the envelope regions from virus strains 85/34 and 84/28 showed that despite significant biological differences, these viruses are closely related to each other and are genotypically more homologous to caprine arthritis-encephalitis virus (CAEV) than to visna virus of sheep. Furthermore, analysis of the nucleotide substitutions in their env regions indicated that when differences between the two Ovine viruses and CAEV were found, the changes often resulted in nucleotides homologous with visna virus. These results suggest that the two field strains of Ovine Lentivirus may have originated from a cross-species infection of sheep by a CAEV-like virus and, evolution of their genomes toward that of Ovine Lentivirus may be reflective of adaptation of these viruses to the new Ovine host.
L Lujan - One of the best experts on this subject based on the ideXlab platform.
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differential infection efficiencies of peripheral lung and tracheal tissues in sheep infected with visna maedi virus via the respiratory tract
Journal of General Virology, 2007Co-Authors: Tom N Mcneilly, L Lujan, Marta M Perez, Peter Tennant, Gordon D. HarkissAbstract:The main routes of transmission of Visna/maedi virus (VMV), an Ovine Lentivirus, are thought to be through ingestion of infected colostrum and/or milk or through inhalation of respiratory secretions. Whereas oral transmission appears to be mediated via epithelial cells within the small intestine, the mechanism of virus uptake in the respiratory tract is unknown. In addition, it is not known whether infection is mediated by cell-associated or cell-free VMV, previous studies having not addressed this question. Intratracheal (i.t.) injection of VMV is known to be a highly efficient method of experimental infection, requiring as little as 101 TCID50 VMV for successful infection. However, using a tracheal organ culture system, we show here that Ovine tracheal mucosa is relatively resistant to VMV, with detectable infection only seen after incubation with high titres of virus (⩾105 TCID50 ml−1). We also demonstrate that i.t. injection results in exposure of both trachea and the lower lung and that the time taken for viraemia and seroconversion to occur after lower lung instillation of VMV was significantly shorter than that observed for tracheal instillation of an identical titre of virus (P=0.030). This indicates that lower lung and not the trachea is a highly efficient site for VMV entry in vivo. Furthermore, cell-free virus was identified within the lung-lining fluid of naturally infected sheep for the first time. Together, these results suggest that respiratory transmission of VMV is mediated by inhalation of aerosols containing free VMV, with subsequent virus uptake in the lower lung.
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a new sensitive serological assay for detection of Lentivirus infections in small ruminants
Clinical and Vaccine Immunology, 1999Co-Authors: Eric Saman, Geertrui Van Eynde, Belén Extramiana, Francesco Tolari, Lorenzo Gonzalez, N J Watt, Gordon D. Harkiss, Beatriz Amorena, L Lujan, Juan Jose BadiolaAbstract:Lentivirus infections in small ruminants represent an economic problem affecting several European countries with important sheep-breeding industries. Programs for control and eradication of these infections are being initiated and require reliable screening assays. This communication describes the construction and evaluation of a new serological screening enzyme-linked immunosorbent assay (ELISA) for the detection of antibodies to maedi-visna virus (MVV) in sheep and to caprine arthritis encephalitis virus (CAEV) in goats. The solid phase is sensitized with a combination of the major core protein p25 of MVV produced in Escherichia coli and a peptide derived from the immunodominant region of the viral transmembrane protein gp46. The peptide carries an N-terminal biotin residue and is complexed with streptavidin prior to being coated. The new assay was evaluated with 2,336 sheep serum samples from different European countries with large differences in the levels of prevalence of MVV infections, and the results have been compared to those of the standard agar gel immunodiffusion test. Discrepant samples were analyzed by Western blotting with viral lysate, and most sera could be classified unambiguously. The estimated overall sensitivity of the new ELISA was 99.4% (95% confidence interval [CI], 98.4 to 99.8%) and the specificity was 99.3% (95% CI, 98.7 to 99.6%). A limited set of goat sera (n 5 212) was also analyzed, with similar results. These data indicate that the new assay is a reliable tool that can be used in control and eradication programs for small ruminant Lentivirus infections. Maedi-visna virus (MVV, also termed Ovine Lentivirus) is a nononcogenic, exogenous retrovirus belonging to the Lentiviridae subfamily and related to human immunodeficiency virus (5, 18, 20). MVV infection in sheep is characterized by a relatively long asymptomatic period in which the virus persists in the presence of a strong humoral and cellular response. Following a variable incubation period (2 to 10 years), the virus may cause a chronic, progressive, inflammatory disease in the lungs, joints, and mammary glands of infected animals. In the central nervous system, inflammation and degenerative processes can result from an MVV infection (2). Caprine arthritis-encephalitis virus (CAEV) is genetically and antigenically closely related to MVV (20). CAEV infection in goats is widespread and may cause important economic losses. The main clinical symptoms are arthritis, chronic subclinical mastitis, and interstitial pneumonia. Encephalitis is often diagnosed in young goats and in adult animals, and encephalitis is seen more frequently than the arthritis observed in MVV-infected sheep. MVV-infected sheep produce high titers of serum antibodies against viral capsid and envelope proteins. Several serological diagnostic tests to detect these antibodies have been described (6, 7, 9, 11, 17, 21), but only two methods, the agar gel immunodiffusion test (AGIDT) and the whole-virus enzymelinked immunosorbent assay (WV-ELISA) are used routinely
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Ovine Lentivirus maedi visna virus protein expression in sheep alveolar macrophages
Veterinary Pathology, 1994Co-Authors: L Lujan, David Collie, I Begara, N J WattAbstract:The expression of gag (p15, p25) and env gene products in Ovine Lentivirus-infected cells was studied in 20 adult Texel ewes seropositive to maedi-visna virus and 10 seronegative matched controls. Bronchoalveolar lavage was performed to recover alveolar cell pools from which cytocentrifuge preparations were made. Single and double immunocytochemical techniques were applied to study viral replication and coexpression of viral markers with markers for macrophages, lymphocytes, and major histocompatibility complex (MHC) class II. Aveolar macrophages of eight of 20 infected sheep (40%) were positive for viral protein expression. The percentage of positive macrophages varied from < 1% to 12% of the total population of macrophages. Viral protein expression was not detected in lymphocytes or other cell types. A relationship between virus-replicating macrophages and differential expression of MHC class II molecules, upregulated in Ovine Lentivirus infection, could not be established. Pathology was evaluated in nine infected ewes. Animals with the highest levels of positive cells had moderate or severe lymphoid interstitial pneumonia. However, sheep with similar degrees of lesions had lower percentages of positive macrophages or were negative for viral protein detection. These results support the idea that a partial or even a complete loss in the restriction mechanism of maedi-visna virus in lungs can occur in some individuals.
David Collie - One of the best experts on this subject based on the ideXlab platform.
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phenotypic analysis of lymphocyte populations in the lungs and regional lymphoid tissue of sheep naturally infected with maedi visna virus
Clinical and Experimental Immunology, 2008Co-Authors: N J Watt, David R Sargan, David Collie, Neil Macintyre, Ian McconnellAbstract:We have analysed the phenotype of lymphocytes in lung and regional lymph node of symptomatic and asymptomatic sheep infected with the Ovine Lentivirus, maedi visna virus (MVV). Compared to equivalent tissues from age-matched, non-infected controls, MVV-infected sheep show increased numbers of lymphocytes in the lung, both in the bronchus-associated lymphoid tissue (BALT) and in the alveolar septae. Both CD8+ and CD4+ T lymphocyte numbers in alveolar septae were increased, particularly in animals with clinical respiratory disease. The ratio of CD8+ to CD4+ lymphocytes was similar to that in normal lung. In both MVV-infected and uninfected animals a high proportion of pulmonary lymphocytes, particularly in the alveolar septae, did not express the CD5 antigen, suggesting that they were activated. The number of activated cells was higher in infected sheep. Variable numbers of alveolar macrophages containing MVV-core protein were present in alveolar lumina, the majority of positive cells showing morphological evidence of activation. In regional lymphoid tissue there were increased numbers of CD8+ and gamma delta expressing T cells in lymphoid follicles and germinal centres of infected animals. The specificity of these cells is unknown and we could find no evidence for the presence of cells productively infected with the virus in these structures. This study shows that activated T lymphocytes, particularly of the CD8 subset, play a major part in the pathogenesis of MVV-induced pulmonary and regional lymph node lesions.
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role of alveolar macrophages in respiratory transmission of visna maedi virus
Journal of Virology, 2008Co-Authors: Tom N Mcneilly, David Collie, Alison Baker, Jeremy K Brown, Gerry Maclachlan, Susan Rhind, Gordon D. HarkissAbstract:A major route of transmission of Visna/maedi virus (VMV), an Ovine Lentivirus, is thought to be via the respiratory tract, by inhalation of either cell-free or cell-associated virus. In previous studies, we have shown that infection via the lower respiratory tract is much more efficient than via upper respiratory tissues (T. N. McNeilly, P. Tennant, L. Lujan, M. Perez, and G. D. Harkiss, J. Gen. Virol. 88:670-679, 2007). Alveolar macrophages (AMs) are prime candidates for the initial uptake of virus in the lower lung, given their in vivo tropism for VMV, abundant numbers, location within the airways, and role in VMV-induced inflammation. Furthermore, AMs are the most likely cell type involved in the transmission of cell-associated virus. In this study, we use an experimental in vivo infection model that allowed the infection of specific segments of the Ovine lung. We demonstrate that resident AMs are capable of VMV uptake in vivo and that this infection is associated with a specific up-regulation of AM granulocyte-macrophage colony-stimulating factor mRNA expression (P < 0.05) and an increase in bronchoalveolar lymphocyte numbers (P < 0.05), but not a generalized inflammatory response 7 days postinfection. We also demonstrate that both autologous and heterologous VMV-infected AMs are capable of transmitting virus after lower, but not upper, respiratory tract instillation and that this transfer of virus appears not to involve the direct migration of virus-infected AMs from the airspace. These results suggest that virus is transferred from AMs into the body via an intermediate route. The results also suggest that the inhalation of infected AMs represents an additional mechanism of virus transmission.
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Ovine Lentivirus maedi visna virus protein expression in sheep alveolar macrophages
Veterinary Pathology, 1994Co-Authors: L Lujan, David Collie, I Begara, N J WattAbstract:The expression of gag (p15, p25) and env gene products in Ovine Lentivirus-infected cells was studied in 20 adult Texel ewes seropositive to maedi-visna virus and 10 seronegative matched controls. Bronchoalveolar lavage was performed to recover alveolar cell pools from which cytocentrifuge preparations were made. Single and double immunocytochemical techniques were applied to study viral replication and coexpression of viral markers with markers for macrophages, lymphocytes, and major histocompatibility complex (MHC) class II. Aveolar macrophages of eight of 20 infected sheep (40%) were positive for viral protein expression. The percentage of positive macrophages varied from < 1% to 12% of the total population of macrophages. Viral protein expression was not detected in lymphocytes or other cell types. A relationship between virus-replicating macrophages and differential expression of MHC class II molecules, upregulated in Ovine Lentivirus infection, could not be established. Pathology was evaluated in nine infected ewes. Animals with the highest levels of positive cells had moderate or severe lymphoid interstitial pneumonia. However, sheep with similar degrees of lesions had lower percentages of positive macrophages or were negative for viral protein detection. These results support the idea that a partial or even a complete loss in the restriction mechanism of maedi-visna virus in lungs can occur in some individuals.
Stephen N. White - One of the best experts on this subject based on the ideXlab platform.
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Genome-Wide Association Identifies Multiple Genomic Regions Associated with Susceptibility to and Control of
2016Co-Authors: Ovine Lentivirus, Stephen N. White, Kreg A. Leymaster, Michelle R. Mousel, Gregory S. Lewis, Lynn M. Herrmann-hoesing, James O. Reynolds, Holly L. Neibergs, Donald P KnowlesAbstract:Background: Like human immunodeficiency virus (HIV), Ovine Lentivirus (OvLV) is macrophage-tropic and causes lifelong infection. OvLV infects one quarter of U.S. sheep and induces pneumonia and body condition wasting. There is no vaccine to prevent OvLV infection and no cost-effective treatment for infected animals. However, breed differences in prevalence and proviral concentration have indicated a genetic basis for susceptibility to OvLV. A recent study identified TMEM154 variants in OvLV susceptibility. The objective here was to identify additional loci associated with odds and/or control of OvLV infection. Methodology/Principal Findings: This genome-wide association study (GWAS) included 964 sheep from Rambouillet, Polypay, and Columbia breeds with serological status and proviral concentration phenotypes. Analytic models accounted for breed and age, as well as genotype. This approach identified TMEM154 (nominal P = 9.261027; empirical P = 0.13), provided 12 additional genomic regions associated with odds of infection, and provided 13 regions associated with control of infection (all nominal P,161025). Rapid decline of linkage disequilibrium with distance suggested many regions included few genes each. Genes in regions associated with odds of infection included DPPA2/DPPA4 (empirical P = 0.006)
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Expanding possibilities for intervention against small ruminant Lentiviruses through genetic marker-assisted selective breeding.
Viruses, 2013Co-Authors: Stephen N. White, Donald P KnowlesAbstract:Small ruminant Lentiviruses include members that infect sheep (Ovine Lentivirus [OvLV]; also known as Ovine progressive pneumonia virus/maedi-visna virus) and goats (caprine arthritis encephalitis virus [CAEV]). Breed differences in seroprevalence and proviral concentration of OvLV had suggested a strong genetic component in susceptibility to infection by OvLV in sheep. A genetic marker test for susceptibility to OvLV has been developed recently based on the TMEM154 gene with validation data from over 2,800 sheep representing nine cohorts. While no single genotype has been shown to have complete resistance to OvLV, consistent association in thousands of sheep from multiple breeds and management conditions highlight a new strategy for intervention by selective breeding. This genetic marker-assisted selection (MAS) has the potential to be a useful addition to existing viral control measures. Further, the discovery of multiple additional genomic regions associated with susceptibility to or control of OvLV suggests that additional genetic marker tests may be developed to extend the reach of MAS in the future. This review will cover the strengths and limitations of existing data from host genetics as an intervention and outline additional questions for future genetic research in sheep, goats, small ruminant Lentiviruses, and their host-pathogen interactions.
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genome wide association identifies multiple genomic regions associated with susceptibility to and control of Ovine Lentivirus
PLOS ONE, 2012Co-Authors: Stephen N. White, Kreg A. Leymaster, Michelle R. Mousel, Lynn M Herrmannhoesing, Donald P Knowles, Gregory S. Lewis, Holly L. Neibergs, James ReynoldsAbstract:BACKGROUND: Like human immunodeficiency virus (HIV), Ovine Lentivirus (OvLV) is macrophage-tropic and causes lifelong infection. OvLV infects one quarter of U.S. sheep and induces pneumonia and body condition wasting. There is no vaccine to prevent OvLV infection and no cost-effective treatment for infected animals. However, breed differences in prevalence and proviral concentration have indicated a genetic basis for susceptibility to OvLV. A recent study identified TMEM154 variants in OvLV susceptibility. The objective here was to identify additional loci associated with odds and/or control of OvLV infection. METHODOLOGY/PRINCIPAL FINDINGS: This genome-wide association study (GWAS) included 964 sheep from Rambouillet, Polypay, and Columbia breeds with serological status and proviral concentration phenotypes. Analytic models accounted for breed and age, as well as genotype. This approach identified TMEM154 (nominal P=9.2×10(-7); empirical P=0.13), provided 12 additional genomic regions associated with odds of infection, and provided 13 regions associated with control of infection (all nominal P<1 × 10(-5)). Rapid decline of linkage disequilibrium with distance suggested many regions included few genes each. Genes in regions associated with odds of infection included DPPA2/DPPA4 (empirical P=0.006), and SYTL3 (P=0.051). Genes in regions associated with control of infection included a zinc finger cluster (ZNF192, ZSCAN16, ZNF389, and ZNF165; P=0.001), C19orf42/TMEM38A (P=0.047), and DLGAP1 (P=0.092). CONCLUSIONS/SIGNIFICANCE: These associations provide targets for mutation discovery in sheep susceptibility to OvLV. Aside from TMEM154, these genes have not been associated previously with lentiviral infection in any species, to our knowledge. Further, data from other species suggest functional hypotheses for future testing of these genes in OvLV and other lentiviral infections. Specifically, SYTL3 binds and may regulate RAB27A, which is required for enveloped virus assembly of human cytomegalovirus. Zinc finger transcription factors have been associated with positive selection for repression of retroviral replication. DLGAP1 binds and may regulate DLG1, a known regulator of HIV infectivity.
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reduced Lentivirus susceptibility in sheep with tmem154 mutations
PLOS Genetics, 2012Co-Authors: Michael P. Heaton, Stephen N. White, Gregory P Harhay, Michael L. Clawson, Kreg A. Leymaster, Timothy P. L. Smith, Michelle R. Mousel, Carol G Chitkomckown, Lynn M Herrmannhoesing, Gregory S. LewisAbstract:Visna/Maedi, or Ovine progressive pneumonia (OPP) as it is known in the United States, is an incurable slow-acting disease of sheep caused by persistent Lentivirus infection. This disease affects multiple tissues, including those of the respiratory and central nervous systems. Our aim was to identify Ovine genetic risk factors for Lentivirus infection. Sixty-nine matched pairs of infected cases and uninfected controls were identified among 736 naturally exposed sheep older than five years of age. These pairs were used in a genome-wide association study with 50,614 markers. A single SNP was identified in the Ovine transmembrane protein (TMEM154) that exceeded genome-wide significance (unadjusted p-value 3×10−9). Sanger sequencing of the Ovine TMEM154 coding region identified six missense and two frameshift deletion mutations in the predicted signal peptide and extracellular domain. Two TMEM154 haplotypes encoding glutamate (E) at position 35 were associated with infection while a third haplotype with lysine (K) at position 35 was not. Haplotypes encoding full-length E35 isoforms were analyzed together as genetic risk factors in a multi-breed, matched case-control design, with 61 pairs of 4-year-old ewes. The odds of infection for ewes with one copy of a full-length TMEM154 E35 allele were 28 times greater than the odds for those without (p-value<0.0001, 95% CI 5–1,100). In a combined analysis of nine cohorts with 2,705 sheep from Nebraska, Idaho, and Iowa, the relative risk of infection was 2.85 times greater for sheep with a full-length TMEM154 E35 allele (p-value<0.0001, 95% CI 2.36–3.43). Although rare, some sheep were homozygous for TMEM154 deletion mutations and remained uninfected despite a lifetime of significant exposure. Together, these findings indicate that TMEM154 may play a central role in Ovine Lentivirus infection and removing sheep with the most susceptible genotypes may help eradicate OPP and protect flocks from reinfection.
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Genome-Wide Association Identifies Multiple Genomic Regions Associated with Susceptibility to and Control of Ovine Lentivirus
2012Co-Authors: Stephen N. White, Kreg A. Leymaster, Michelle R. Mousel, Gregory S. Lewis, Lynn M. Herrmann-hoesing, James O. Reynolds, Holly L. Neibergs, Donald P KnowlesAbstract:BackgroundLike human immunodeficiency virus (HIV), Ovine Lentivirus (OvLV) is macrophage-tropic and causes lifelong infection. OvLV infects one quarter of U.S. sheep and induces pneumonia and body condition wasting. There is no vaccine to prevent OvLV infection and no cost-effective treatment for infected animals. However, breed differences in prevalence and proviral concentration have indicated a genetic basis for susceptibility to OvLV. A recent study identified TMEM154 variants in OvLV susceptibility. The objective here was to identify additional loci associated with odds and/or control of OvLV infection. Methodology/Principal FindingsThis genome-wide association study (GWAS) included 964 sheep from Rambouillet, Polypay, and Columbia breeds with serological status and proviral concentration phenotypes. Analytic models accounted for breed and age, as well as genotype. This approach identified TMEM154 (nominal P = 9.2×10−7; empirical P = 0.13), provided 12 additional genomic regions associated with odds of infection, and provided 13 regions associated with control of infection (all nominal P
