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Ovine gammaherpesvirus 2 infections in cattle without typical manifestations of sheep-associated malignant catarrhal fever and concomitantly infected with bovine coronavirus

ABSTRACT: Sheep-associated malignant catarrhal fever (SA-MCF) is a severe, frequently fatal, lymphoproliferative disease that affects a wide variety of ruminants and is caused by ovine gammaherpesvirus 2 (OvHV-2), a member of the MCF virus (MCFV) complex. The typical clinical manifestations of SA-MCF are well known and easily recognized by veterinarians, resulting in clinical diagnosis of MCF when characteristic clinical signs are present. This article describes the findings observed in cattle infected with OvHV-2 but without typical clinical manifestations of SA-MCF. Three calves with episodes of diarrhea before death and a yearling that died suddenly were investigated. Gross alterations were not suggestive of SA-MCF. Histopathology revealed a combination of proliferating vascular lesions (PVLs) and necrotizing vasculitis in three animals (two calves and the yearling); with PVLs being identified only at the carotid rete mirabile of two calves infected with OvHV-2. Additional significant histopathologic lesions included atrophic enteritis, portal lymphocytic hepatitis, interstitial pneumonia, suppurative bacterial bronchopneumonia, and pulmonary hemorrhage. An immunohistochemical assay designed to identify only antigens of MCFV revealed, positive, intralesional, intracytoplasmic immunoreactivity within epithelial cells of multiple tissues of all animals with PVLs. PCR assays amplified OvHV-2 DNA from multiple tissues of the animals that contained MCFV proteins, confirming the MCFV identified as OvHV-2. Additionally, bovine coronavirus (BCoV) nucleic acids were amplified from tissues of all animals, including the animal not infected by OvHV-2. Collectively, these findings confirmed the participation of OvHV-2 in the development of the disease patterns observed in these animals that were concomitantly infected by BCoV and provide additional confirmation that cattle can be subclinically infected with OvHV-2. Consequently, the real occurrence of OvHV-2-related disease may be more elevated than reported, since asymptomatic or subclinically infected animals are not likely to be investigated for OvHV-2. Furthermore, PVLs should be included as possible histologic indicators of OvHV-2-related diseases in ruminants.

Supplementary Information

The online version contains supplementary material available at 10.1007/s42770-021-00653-6.

SUBMITTER: Headley S

PROVIDER: S-EPMC8590972 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Ovine gammaherpesvirus 2 (OvHV-2), a member of the genus Macavirus, causes sheep-associated malignant catarrhal fever (SA-MCF), a fatal lymphoproliferative disease affecting a wide variety of ungulates in addition to horses. This study described an outbreak of SA-MCF in Mexico and the identification of the OvHV-2 virus in primary rabbit testis cultures through the generation of intranuclear inclusion bodies, syncytia, immunofluorescence (IF), immunocytochemistry (ICC), immunohistochemistry (IHC), endpoint polymerase chain reaction (PCR), and partial sequencing of the ORF75 gene. The animals involved in this outbreak showed mucogingival ulcers in the vestibule of the mouth and tongue, hypersalivation, corneal opacity, reduced food consumption, and weight loss of variable severity. These clinical signs and the histopathological findings suggested the diagnosis of SA-MCF. Buffy coat fractions from the anticoagulated blood samples of ill animals were collected and analyzed by PCR. Positive buffy coats were used to inoculate the primary cell cultures of rabbit testis to identify the virus. Small clusters of refractile cytomegalic cells, characteristic of viral cytopathic effects, were observed between 48 and 72 h post-infection. Furthermore, intranuclear acidophilic inclusion bodies (IBs) were identified in the inoculated primary culture cells, and the cytoplasm showed immunoreactivity with hyperimmune rabbit serum against OvHV-2. Moreover, in the liver histological sections from sick deer, immunoreactive juxtanuclear IBs were identified with the same rabbit hyperimmune serum. The obtained sequences were aligned with the OvHV-2 sequences reported in GenBank and revealed a nucleotide identity higher than 98%. Based on the evidence provided in this study, we conclude that the outbreak of SA-MCF in the municipality of Tequisquiapan in the state of Queretaro, Mexico, was caused by OvHV-2. This is the second study reporting that horses are susceptible to OvHV-2 infection and can develop SA-MCF. We identified for the first time in Mexico, the presence of OvHV-2 in buffy coats from horses and Artiodactyla.

Project description:BackgroundMalignant catarrhal fever (MCF) is a lethal disease of cattle, characterized by vasculitis, necrosis, and accumulation of activated, dysregulated cytotoxic lymphocytes in various tissues. Ovine gamma herpesvirus 2 (OvHV-2) is a causative agent of MCF, which may trigger the disease through immunopathogenic pathways. Lymphocytes are the main target of the virus. However, the pathogenic basis of the disease is still mysterious.Methods/findingsWe hypothesized that the gene expression patterns of OvHV-2 and the relative abundances of host cell transcripts in lymphnodes may be used to identify pathways that help to explain the pathogenesis of MCF. Therefore, viral and host cell gene expression patterns in lymph nodes of animals with MCF and healthy controls were analyzed by microarray. Two regions on the viral genome were transcriptionally active, one encoding an orthologue to the latency-associated nuclear antigen (ORF73) of other gamma herpesviruses, the other with no predicted open reading frame. A vast number of transcripts related to inflammatory processes, lymphocyte activation, cell proliferation and apoptosis were detected at different abundances. However, the IL-2 transcript was eminent among the transcripts, which were, compared to healthy controls, less abundant in animals with MCF. The ratio between CD4- and CD8-positive T-lymphocytes was decreased in the lymphnodes of animals with MCF compared to healthy controls. In contrast, the same ratio was stable, when peripheral blood lymphocytes were analyzed.Conclusions/significanceThe phenotype of mice with a deficient IL-2-system almost perfectly matches the clinical signs observed in cattle with MCF, which feature a significantly decreased IL-2 transcript abundance, compared to healthy cattle. This supports the hypothesis that immunopathogenic events are linked to the pathogenesis of MCF. IL-2-deficiency may play an important role in the process. Therefore, this work opens new avenues for research on MCF.

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Ovine gammaherpesvirus 2 infections in cattle without typical manifestations of sheep-associated malignant catarrhal fever and concomitantly infected with bovine coronavirus

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