Abstract
Bovine viral diarrhea virus (BVDV) infection during early gestation results in persistently infected (PI) immunotolerant calves that are the primary reservoirs of the virus. Pathologies observed in PI cattle include congenital defects of the brain, heart, and bone as well as marked functional defects in their immune system. It was hypothesized that fetal BVDV infection alters T cell activation and signaling genes by epigenetic mechanisms. To test this, PI and control fetal splenic tissues were collected on day 245 of gestation, 170 days post maternal infection. DNA was isolated for reduced representation bisulfite sequencing, protein was isolated for proteomics, both were analyzed with appropriate bioinformatic methods. Within set parameters, 1951 hypermethylated and 691 hypomethylated DNA regions were identified in PI compared to control fetuses. Pathways associated with immune system, neural, cardiac, and bone development were associated with heavily methylated DNA. The proteomic analysis revealed 12 differentially expressed proteins in PI vs. control animals. Upregulated proteins were associated with protein processing, whereas downregulated proteins were associated with lymphocyte migration and development in PI compared to control fetal spleens. The epigenetic changes in DNA may explain the immune dysfunctions, abnormal bone formation, and brain and heart defects observed in PI animals.
Highlights
Bovine viral diarrhea virus (BVDV) is a single stranded RNA virus in the familyFlaviviridae and Pestivirus genus, discovered in 1946 [1–5]
Most BVDV infections of healthy adult cattle result in subclinical to relatively mild disease depending on the strain of virus; severe pathologies occur in fetal infections following the vertical transmission from dam to fetus [12–14]
There were 2641 differentially methylated regions (DMRs) between control and persistently infected (PI) animals. Of those DMRs, 1951 regions were hypermethylated in PI animals compared to controls while 691 regions were hypomethylated in PIs compared to controls
Summary
Bovine viral diarrhea virus (BVDV) is a single stranded RNA virus in the familyFlaviviridae and Pestivirus genus, discovered in 1946 [1–5]. Most BVDV infections of healthy adult cattle result in subclinical to relatively mild disease depending on the strain of virus; severe pathologies occur in fetal infections following the vertical transmission from dam to fetus [12–14]. The outcome of BVDV fetal infection is determined by the time of infection relative to the development of the fetal bovine immune system [12–14]. If fetal BVDV infection occurs between gestational days 42 and 125, the fetus is unable to mount a competent immune response, becomes immunotolerant and persistently infected (PI), shedding the virus throughout its postnatal life [15,16]. Fetuses infected after day 150 of gestation are able to mount a more mature immune response to BVDV as evidenced by the presence of virus-specific antibodies and clearance of the virus prior to birth [12]
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