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Up-regulation of Fetal Cardiac Genes following Persistent and Transient Bovine Viral Diarrhea Virus Infection
Transplacental infection by non-cytopathic (ncp) bovine viral diarrhea virus (BVDV) during early gestation results in persistently infected (PI) fetuses with lifelong viremia. Conversely, infection of ncp BVDV later in gestation (~day 150) or after birth leads to transient infection (TI). We hypothesized that ncp BVDV infection of the dam would alter gene expression related to development of fetal heart and vascular remodeling. Gene expression in the right ventricular heart (RV) of uninfected bovine fetuses was compared to PI and TI fetuses. Naïve pregnant heifers were challenged with 2 ml of ncp BVDV (4.4 log10 TCID50/mL) on day 75 (PI fetus; n = 6) or day 175 (TI fetus, n = 6) or kept uninfected (Control fetus; n =6). Maternal blood ncp BVDV RNA increased in concentration following PI and TI and then diminished. Fetuses were collected via Cesarean section and necropsied on day 190 of pregnancy. To examine fetal cardiac gene expression, quantitative real-time PCR was completed. Data were analyzed using PROC GLM procedure of SAS. BVDV RNA concentration in the RV was greater in PI fetuses when compared to uninfected control and TI fetuses (P < 0.05). BVDV was not detected in TI fetal heart because of clearance of virus between days 175 and 190. Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) act to reduce blood pressure. The mRNA concentrationsfor ANP and BNP were greater (P < 0.05) in RV of the TI fetuses, when compared with controls. Vascular endothelial growth factor (VEGF; angiogenic) and cyclin D1 (marker for left ventricular hypertrophy) mRNA concentrations were upregulated (P < 0.05) in TI fetuses. Fibroblast growth factor receptor1 (FGFR1; angiogenic) mRNA concentration was greater in RV of PI and TI fetuses (P < 0.05). Chemokine ligand 12 (CXCL12) and its receptor, chemokine receptor4 (CXCR4) facilitate fetal cardiac development and may assist in remodeling/repair following acute myocardial infarction. Concentrations of the mRNAs encoding CXCL12 and CXCR4 tended to be upregulated in RV of TI fetuses (P = 0.0860, P= 0.0951; respectively). Maternal ncp BVDV infection may impaired fetal cardiac developmentvia up-regulation of vascular regulatory, cardiac remodeling and angiogenic genes regardless of TI or PI. USDA NIFA AFRI 2008-35204-04652.
Keywords: Bovine viral diarrhea virus, Fetus, Heart