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

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. Overall design: Reduced-representation bisulfite sequencing (RRBS-Seq ) for five randomly selected 4 month old calves known to be seronegative for BVDV and five age-matched calves known to be persistently infected with BVDV. Jugular vein was collected, and PMBC were collected for DNA analysis.