title: Induction of interferon-gamma and downstream pathways during establishment of fetal persistent infection with bovine viral diarrhea virus.
abstract: Development of transplacental infection depends on the ability of the virus to cross the placenta and replicate within the fetus while counteracting maternal and fetal immune responses. Unfortunately, little is known about this complex process. Non-cytopathic (ncp) strains of bovine viral diarrhea virus (BVDV), a pestivirus in the Flaviviridae family, cause persistent infection in early gestational fetuses (<150 days; persistently infected, PI), but are cleared by immunocompetent animals and late gestational fetuses (>150 days; transiently infected, TI). Evasion of innate immune response and development of immunotolerance to ncp BVDV have been suggested as possible mechanisms for the establishment of the persistent infection. Previously we have observed a robust temporal induction of interferon (IFN) type I (innate immune response) and upregulation of IFN stimulated genes (ISGs) in BVDV TI fetuses. Modest chronic upregulation of ISGs in PI fetuses and calves reflects a stimulated innate immune response during persistent BVDV infection. We hypothesized that establishing persistent fetal BVDV infection is also accompanied by the induction of IFN-gamma (IFN-γ). The aims of the present study were to determine IFN-γ concentration in blood and amniotic fluid from control, TI and PI fetuses during BVDV infection and analyze induction of the IFN-γ downstream pathways in fetal lymphoid tissues. Two experiments with in vivo BVDV infections were completed. In Experiment 1, pregnant heifers were infected with ncp BVDV type 2 on day 75 or 175 of gestation or kept naïve to generate PI, TI and control fetuses, respectively. Fetuses were collected by Cesarean section on day 190. In Experiment 2, fetuses were collected on days 82, 89, 97, 192 and 245 following infection of pregnant heifers on day 75 of gestation. The results were consistent with the hypothesis that ncp BVDV infection induces IFN-γ secretion during acute infection in both TI and PI fetuses and that lymphoid tissues such as spleen, liver and thymus, serve both as possible sources of IFN-γ and target organs for its effects. Notably, induction of IFN-γ coincides with a decrease in BVDV RNA concentrations in PI fetal blood and tissues. This is the first report indicating the possible presence of an adaptive immune response in persistent BVDV infections, which may be contributing to the observed reduction of viremia in PI fetuses.
authors: Animal Reproduction and Biotechnology Laboratory, Department of Biomedical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, 1683 Campus Delivery, Fort Collins, CO 80523-1683, USA. Electronic address: Natalia.Smirnova@colostate.edu.
authors: Natalia P
authors: NP
authors: Smirnova
authors: Animal Reproduction and Biotechnology Laboratory, Department of Biomedical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, 1683 Campus Delivery, Fort Collins, CO 80523-1683, USA; Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, 1619 Campus Delivery, Fort Collins, CO 80523-1619, USA. Electronic address: Brett.Webb@ndsu.edu.
authors: Brett T
authors: BT
authors: Webb
authors: Ruminant Diseases and Immunology Unit, National Animal Disease Center, USDA/ARS, Ames, IA 50010, USA. Electronic address: Jodi.McGill@ars.usda.gov.
authors: Jodi L
authors: JL
authors: McGill
authors: Ruminant Diseases and Immunology Unit, National Animal Disease Center, USDA/ARS, Ames, IA 50010, USA. Electronic address: Robert-Schaut@uiowa.edu.
authors: Robert G
authors: RG
authors: Schaut
authors: Australian Infectious Diseases Research Centre, University of Queensland, St. Lucia, Qld 4067, Australia; School of Veterinary Science, University of Queensland, Gatton Campus, Qld 4343, Australia. Electronic address: h.bielefeldtohmann1@uq.edu.au.
authors: Helle
authors: H
authors: Bielefeldt-Ohmann
authors: Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, 1619 Campus Delivery, Fort Collins, CO 80523-1619, USA. Electronic address: Hana.Van_Campen@Colostate.edu.
authors: Hana
authors: H
authors: Van Campen
authors: Ruminant Diseases and Immunology Unit, National Animal Disease Center, USDA/ARS, Ames, IA 50010, USA. Electronic address: Randy.Sacco@ars.usda.gov.
authors: Randy E
authors: RE
authors: Sacco
authors: Animal Reproduction and Biotechnology Laboratory, Department of Biomedical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, 1683 Campus Delivery, Fort Collins, CO 80523-1683, USA. Electronic address: Thomas.Hansen@colostate.edu.
authors: Thomas R
authors: TR
authors: Hansen
mesh_terms: D000653:Amniotic Fluid / Q000737:chemistry; D000818:Animals; D001769:Blood / Q000821:virology; D001774:Blood Chemical Analysis; D002417:Cattle; D002418:Cattle Diseases / Q000276:immunology* / Q000821:virology*; D030242:Diarrhea Virus 2, Bovine Viral / Q000276:immunology*; D005260:Female; D005315:Fetal Diseases / Q000276:immunology / Q000662:veterinary* / Q000821:virology; D005333:Fetus / Q000821:virology; D007371:Interferon-gamma / Q000032:analysis*; D008099:Liver / Q000276:immunology; D018182:Pestivirus Infections / Q000276:immunology / Q000662:veterinary* / Q000821:virology; D011247:Pregnancy; D012367:RNA, Viral / Q000097:blood; D013154:Spleen / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology
chemical_list: D012367:RNA, Viral; D007371:Interferon-gamma
keywords: Bovine viral diarrhea virus; Chemokines; Fetus; Immune response; Interferon-gamma; Persistent infection