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Immunophenotyping of inflammatory cells associated with Schmallenberg virus infection of the central nervous system of ruminants.

Herder V, Hansmann F, Wohlsein P, Peters M, Varela M, Palmarini M, Baumgärtner W - PLoS ONE (2013)

Bottom Line: Malformations like por- and hydranencephaly, frequently found in the temporal lobe, showed associated demyelination and axonal loss.Highest amounts of virus-protein expression levels were found in the temporal lobe.Our findings suggest that: (i) different brain regions display differential susceptibility to SBV infection; (ii) inflammatory cells in the CNS are found only in a minority of virus infected animals; (iii) malformations occur in association with and without inflammation in the CNS; and (iv) viral antigen is strongly associated with the presence of inflammation in naturally infected animals.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Veterinary Medicine, Hannover, Lower Saxony, Germany.

ABSTRACT
Schmallenberg virus (SBV) is a recently discovered Bunyavirus associated mainly with abortions, stillbirths and malformations of the skeletal and central nervous system (CNS) in newborn ruminants. In this study, a detailed immunophenotyping of the inflammatory cells of the CNS of affected animals was carried out in order to increase our understanding of SBV pathogenesis. A total of 82 SBV-polymerase chain reaction (PCR) positive neonatal ruminants (46 sheep lambs, 34 calves and 2 goat kids) were investigated for the presence of inflammation in the brain and spinal cord. The study focused on 15 out of 82 animals (18.3%) showing inflammation in the CNS. All 15 neonates displayed lymphohistiocytic meningoencephalomyelitis affecting most frequently the mesencephalon and the parietal and temporal lobes. The majority of infiltrating cells were CD3-positive T cells, followed by CD79α-positive B cells and CD68-positive microglia/macrophages. Malformations like por- and hydranencephaly, frequently found in the temporal lobe, showed associated demyelination and axonal loss. SBV antigen was detected in 37 out of 82 (45.1%) neonatal brains by immunohistochemistry. In particular, SBV antigen was found in 93.3% (14 out of 15 ruminants) and 32.8% (22 out of 67 ruminants) of animals with and without encephalitis, respectively. Highest amounts of virus-protein expression levels were found in the temporal lobe. Our findings suggest that: (i) different brain regions display differential susceptibility to SBV infection; (ii) inflammatory cells in the CNS are found only in a minority of virus infected animals; (iii) malformations occur in association with and without inflammation in the CNS; and (iv) viral antigen is strongly associated with the presence of inflammation in naturally infected animals. Further studies are required to explore the cell tropism and pathogenesis of SBV infection in ruminants.

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Histopathology and distribution pattern of inflammation in naturally with SBV-infected neonatal ruminants (n = 15) of the central nervous system (HE-staining).A) Spinal cord of a sheep displaying mild, multifocal lymphohistiocytic infiltrates in meninges, perivascular spaces and the parenchyma of gray and white matter (animal no 4; C = central canal; F = fissura mediana ventralis; bar, 1000 µm). B) Moderate perivascular infiltrates characterized by lymphocytes and macrophages in the brain of a SBV-infected sheep (animal no 10; bar, 20 µm). C) Coronal section of a brain showing the mesencephalon, hippocampus, lateral ventricle as well as parietal and temporal lobes. The temporal lobe of this sheep lamb displays a porencephaly with complete loss of the white matter in the center (asterisk; animal no 5; M = mesencephalon; bar, 5000 µm). D) Topographic map of a coronal brain section displaying parietal, temporal lobes, mesencephalon and hippocampus summarizing the percentages of histologic findings in all investigated animals with respected to specific brain regions. E) Percentages of brain regions displaying inflammatory changes in ruminants with SBV infection. F) Occurrence of CNS malformations in SBV-infected animals associated with (n = 15) and without inflammation (n = 72). Percentages of animals displaying cerebellar hypoplasia (CH), porencephaly (P), hydranencephaly (H), hydrocephalus internus (HI) and no malformations (none) are given. Absolute numbers of affected animals are given on top of the bar. Note, that one animal exhibited more than one malformation.
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pone-0062939-g001: Histopathology and distribution pattern of inflammation in naturally with SBV-infected neonatal ruminants (n = 15) of the central nervous system (HE-staining).A) Spinal cord of a sheep displaying mild, multifocal lymphohistiocytic infiltrates in meninges, perivascular spaces and the parenchyma of gray and white matter (animal no 4; C = central canal; F = fissura mediana ventralis; bar, 1000 µm). B) Moderate perivascular infiltrates characterized by lymphocytes and macrophages in the brain of a SBV-infected sheep (animal no 10; bar, 20 µm). C) Coronal section of a brain showing the mesencephalon, hippocampus, lateral ventricle as well as parietal and temporal lobes. The temporal lobe of this sheep lamb displays a porencephaly with complete loss of the white matter in the center (asterisk; animal no 5; M = mesencephalon; bar, 5000 µm). D) Topographic map of a coronal brain section displaying parietal, temporal lobes, mesencephalon and hippocampus summarizing the percentages of histologic findings in all investigated animals with respected to specific brain regions. E) Percentages of brain regions displaying inflammatory changes in ruminants with SBV infection. F) Occurrence of CNS malformations in SBV-infected animals associated with (n = 15) and without inflammation (n = 72). Percentages of animals displaying cerebellar hypoplasia (CH), porencephaly (P), hydranencephaly (H), hydrocephalus internus (HI) and no malformations (none) are given. Absolute numbers of affected animals are given on top of the bar. Note, that one animal exhibited more than one malformation.

Mentions: Inflammatory changes of brain and/or meninges were detected in 15 (18.3%) of 82 ruminant neonates naturally infected with SBV. More specifically, inflammation was detected in 13 out of 46 sheep lambs (28.3%), 1 out of 34 calf (2.9%) and in 1 out of 2 goat kids (50%). In order to characterize the topography of the inflammatory process, 9 CNS areas were evaluated and scored individually. Inflammatory changes were characterized by lymphohistiocytic perivascular cuffs with few plasma cells and variable numbers of cell layers and parenchymal infiltrates in the gray and white matter of the brain, spinal cord and the meninges (Fig. 1A–B). The mesencephalon was affected in 13 of 15 cases, and parietal and temporal lobes in 11 of 15 cases. The hippocampus and occipital lobes displayed inflammation in 8 out of 15 brains, whereas only 7 out of 15 animals exhibited inflammation in the frontal lobe and brain stem. The cerebellum and medulla oblongata were less often affected (5 and 6 of 15 cases, respectively) than other areas of the brain. In addition, lymphohistiocytic infiltrates were also found adjacent and distant to malformations like porencephaly (Fig. 1C). A schematic overview of the region-specific occurrence of the inflammation is given in Figure 1D–E.


Immunophenotyping of inflammatory cells associated with Schmallenberg virus infection of the central nervous system of ruminants.

Herder V, Hansmann F, Wohlsein P, Peters M, Varela M, Palmarini M, Baumgärtner W - PLoS ONE (2013)

Histopathology and distribution pattern of inflammation in naturally with SBV-infected neonatal ruminants (n = 15) of the central nervous system (HE-staining).A) Spinal cord of a sheep displaying mild, multifocal lymphohistiocytic infiltrates in meninges, perivascular spaces and the parenchyma of gray and white matter (animal no 4; C = central canal; F = fissura mediana ventralis; bar, 1000 µm). B) Moderate perivascular infiltrates characterized by lymphocytes and macrophages in the brain of a SBV-infected sheep (animal no 10; bar, 20 µm). C) Coronal section of a brain showing the mesencephalon, hippocampus, lateral ventricle as well as parietal and temporal lobes. The temporal lobe of this sheep lamb displays a porencephaly with complete loss of the white matter in the center (asterisk; animal no 5; M = mesencephalon; bar, 5000 µm). D) Topographic map of a coronal brain section displaying parietal, temporal lobes, mesencephalon and hippocampus summarizing the percentages of histologic findings in all investigated animals with respected to specific brain regions. E) Percentages of brain regions displaying inflammatory changes in ruminants with SBV infection. F) Occurrence of CNS malformations in SBV-infected animals associated with (n = 15) and without inflammation (n = 72). Percentages of animals displaying cerebellar hypoplasia (CH), porencephaly (P), hydranencephaly (H), hydrocephalus internus (HI) and no malformations (none) are given. Absolute numbers of affected animals are given on top of the bar. Note, that one animal exhibited more than one malformation.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3646890&req=5

pone-0062939-g001: Histopathology and distribution pattern of inflammation in naturally with SBV-infected neonatal ruminants (n = 15) of the central nervous system (HE-staining).A) Spinal cord of a sheep displaying mild, multifocal lymphohistiocytic infiltrates in meninges, perivascular spaces and the parenchyma of gray and white matter (animal no 4; C = central canal; F = fissura mediana ventralis; bar, 1000 µm). B) Moderate perivascular infiltrates characterized by lymphocytes and macrophages in the brain of a SBV-infected sheep (animal no 10; bar, 20 µm). C) Coronal section of a brain showing the mesencephalon, hippocampus, lateral ventricle as well as parietal and temporal lobes. The temporal lobe of this sheep lamb displays a porencephaly with complete loss of the white matter in the center (asterisk; animal no 5; M = mesencephalon; bar, 5000 µm). D) Topographic map of a coronal brain section displaying parietal, temporal lobes, mesencephalon and hippocampus summarizing the percentages of histologic findings in all investigated animals with respected to specific brain regions. E) Percentages of brain regions displaying inflammatory changes in ruminants with SBV infection. F) Occurrence of CNS malformations in SBV-infected animals associated with (n = 15) and without inflammation (n = 72). Percentages of animals displaying cerebellar hypoplasia (CH), porencephaly (P), hydranencephaly (H), hydrocephalus internus (HI) and no malformations (none) are given. Absolute numbers of affected animals are given on top of the bar. Note, that one animal exhibited more than one malformation.
Mentions: Inflammatory changes of brain and/or meninges were detected in 15 (18.3%) of 82 ruminant neonates naturally infected with SBV. More specifically, inflammation was detected in 13 out of 46 sheep lambs (28.3%), 1 out of 34 calf (2.9%) and in 1 out of 2 goat kids (50%). In order to characterize the topography of the inflammatory process, 9 CNS areas were evaluated and scored individually. Inflammatory changes were characterized by lymphohistiocytic perivascular cuffs with few plasma cells and variable numbers of cell layers and parenchymal infiltrates in the gray and white matter of the brain, spinal cord and the meninges (Fig. 1A–B). The mesencephalon was affected in 13 of 15 cases, and parietal and temporal lobes in 11 of 15 cases. The hippocampus and occipital lobes displayed inflammation in 8 out of 15 brains, whereas only 7 out of 15 animals exhibited inflammation in the frontal lobe and brain stem. The cerebellum and medulla oblongata were less often affected (5 and 6 of 15 cases, respectively) than other areas of the brain. In addition, lymphohistiocytic infiltrates were also found adjacent and distant to malformations like porencephaly (Fig. 1C). A schematic overview of the region-specific occurrence of the inflammation is given in Figure 1D–E.

Bottom Line: Malformations like por- and hydranencephaly, frequently found in the temporal lobe, showed associated demyelination and axonal loss.Highest amounts of virus-protein expression levels were found in the temporal lobe.Our findings suggest that: (i) different brain regions display differential susceptibility to SBV infection; (ii) inflammatory cells in the CNS are found only in a minority of virus infected animals; (iii) malformations occur in association with and without inflammation in the CNS; and (iv) viral antigen is strongly associated with the presence of inflammation in naturally infected animals.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Veterinary Medicine, Hannover, Lower Saxony, Germany.

ABSTRACT
Schmallenberg virus (SBV) is a recently discovered Bunyavirus associated mainly with abortions, stillbirths and malformations of the skeletal and central nervous system (CNS) in newborn ruminants. In this study, a detailed immunophenotyping of the inflammatory cells of the CNS of affected animals was carried out in order to increase our understanding of SBV pathogenesis. A total of 82 SBV-polymerase chain reaction (PCR) positive neonatal ruminants (46 sheep lambs, 34 calves and 2 goat kids) were investigated for the presence of inflammation in the brain and spinal cord. The study focused on 15 out of 82 animals (18.3%) showing inflammation in the CNS. All 15 neonates displayed lymphohistiocytic meningoencephalomyelitis affecting most frequently the mesencephalon and the parietal and temporal lobes. The majority of infiltrating cells were CD3-positive T cells, followed by CD79α-positive B cells and CD68-positive microglia/macrophages. Malformations like por- and hydranencephaly, frequently found in the temporal lobe, showed associated demyelination and axonal loss. SBV antigen was detected in 37 out of 82 (45.1%) neonatal brains by immunohistochemistry. In particular, SBV antigen was found in 93.3% (14 out of 15 ruminants) and 32.8% (22 out of 67 ruminants) of animals with and without encephalitis, respectively. Highest amounts of virus-protein expression levels were found in the temporal lobe. Our findings suggest that: (i) different brain regions display differential susceptibility to SBV infection; (ii) inflammatory cells in the CNS are found only in a minority of virus infected animals; (iii) malformations occur in association with and without inflammation in the CNS; and (iv) viral antigen is strongly associated with the presence of inflammation in naturally infected animals. Further studies are required to explore the cell tropism and pathogenesis of SBV infection in ruminants.

Show MeSH
Related in: MedlinePlus