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Epigenomic alterations in the postnatal period of calves persistently infected with bovine viral diarrhea virus

ABSTRACT: Bovine Viral Diarrhea Virus (BVDV) is a globally prevalent pathogen that causes severe detriment within the commercial cattle industry. BVDV is a vertically transmissible virus that can cross the placenta, infecting both fetus and dam. Infection occurring before the development of the fetal adaptive immune response, prior to approximately 125 days of gestation, results in a persistently infected (PI) calf. The PI calf is unable to produce BVDV specific antibodies, is immunotolerant, and sheds virus consistently. PI fetuses display alterations of the methylome and proteome at day 245 of gestation corresponding to pathologies of the immune system, bone, brain, and heart. It was hypothesized that epigenetic alterations observed in the prenatal period are a remnant of fetal programming due to fetal BVDV infection and persist into the postnatal period. To test this hypothesis, white blood cells were isolated from whole blood collected from 5 PI and 5 control heifers at 4 months of age and subjected to reduced representation bisulfite sequencing. Analysis of the methylome at 4 months of age indicated that 5,349 (64%) of the identified differentially methylated CpG sites (DMSs) were hypomethylated and 3,018 (36%) of DMSs were hypermethylated. Genes in which DMSs were identified were associated with the immune system, hematopoiesis, and the cardiac system. Complete blood count and flow cytometry data corroborate abnormalities of the immune response. Data presented here introduces a new perspective on the predisposition of PI cattle to fatal secondary infections.

ORGANISM(S): Bos taurus

PROVIDER: GSE271244 | GEO | 2025/05/30

REPOSITORIES: GEO

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Project description:Bovine Viral Diarrhea Virus (BVDV) is the most detrimental flavivirus within the cattle industry. Infection with vertically transmissible BVDV prior to 125 days of gestation results in the generation of a persistently infected (PI) calf. These PI calves are unable to clear the virus in utero, due to an incomplete immune response. However, when infection with BVDV occurs after 150 days of gestation, the fetus clears the transient infection (TI) in utero and is born with BVDV specific antibodies. Variations in DNA methylation have been identified in white blood cells (WBC) of TI heifers at birth. It was hypothesized that epigenomic alterations persist into the postnatal period and lead to previously undocumented pathologies. To study these possible effects, DNA was isolated from the WBCs of 5 TI heifers and 5 control heifers at 4 months of age and subjected to reduced representation bisulfite sequencing (RRBS). Differential analysis of the methylome revealed a total of 3,047 differentially methylated CpG sites (DMSs), 1,349 of which were hypermethylated and 1,698 were hypomethylated. Genes containing differential methylation were associated with inflammation, reactive oxygen species (ROS) production, and metabolism. Complete blood count (CBC) data identified a higher lymphocyte percentage in TI heifers. When compared in the context of the CD45+ parent population, spectral flow cytometry revealed increased intermediate monocytes, B cells, and CD25+/CD127- T cells, and decreased CD4+/CD8b+ T cells. Comparative analysis revealed differential methylation of CpG sites contained in 205 genes, 5 promoters, and 10 CpG islands at birth that were also present at 4 months of age. Comparison of differential methylation in TI heifers and PI heifers at 4 months of age showed 465 genes, 18 promoters, and 34 CpG islands in common. Differential methylation of WBC DNA persists to 4 months of age in TI heifers and is associated with dysregulation of inflammation, metabolism, and growth. Analysis of differential methylation in TI heifers contributes to the understanding of how fetal infection with BVDV induces postnatal detriments related to profit loss.

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Epigenomic alterations in the postnatal period of calves persistently infected with bovine viral diarrhea virus

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