Induction of interferon-gamma and downstream pathways during establishment of fetal persistent infection with bovine viral diarrhea virus

Authors: SMIRNOVA, NATALIS - Colorado State University; WEBB, BRETT - Colorado State University; McGill, Jodi; SCHAUT, ROBERT - University Of Iowa; BIELEFELDT-OHMANN, HELLE - University Of Queensland; VAN CAMPEN, HANA - Colorado State University; Sacco, Randy; HANSEN, THOMAS - Colorado State University

Submitted to: Virus Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/3/2014
Publication Date: 4/1/2014
Publication URL: http://handle.nal.usda.gov/10113/61553
Citation: Smirnova, N.P., Webb, B.T., McGill, J.L., Schaut, R.G., Bielefeldt-Ohmann, H., Van Campen, H., Sacco, R.E., Hansen, T.R. 2014. Induction of interferon-gamma and downstream pathways during establishment of fetal persistent infection with bovine viral diarrhea virus. Virus Research. 183:95-106. DOI: 10.1016/j.virusres.2014.02.002.

Interpretive Summary: Bovine viral diarrhea virus (BVDV) infects cattle worldwide resulting in disease in both dairy and beef production units. Frequently BVDV is introduced into a production unit by the by entry of an animal persistently infected (PI) with BVDV. PI animals are the result of the infection of a fetus before the maturation of the immune system. This infection results in an animal that produces virus and sheds it to its pen mates throughout its lifetime. In the present study, researchers from Colorado State University, School of Veterinary Science in Queensland, Australia, and the National Animal Disease Center studied immune responses following fetal infection with BVDV. Female cattle were infected with the virus and fetuses were collected on different days of pregnancy. The results show that BVDV causes secretion of a certain immune protein in the blood of fetuses during an acute infection. These data provide novel information on the impact of fetal infection with this cattle virus. Scientists trying to investigate methods to prevent development of PI animals would be beneficiaries of this current research, with the ultimate goal of providing intervention strategies to cattle producers.

Technical 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 from 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 temporal induction of a robust interferon (IFN) type I (innate immune) response and up regulation of IFN stimulated genes (ISGs) in BVDV TI fetuses. Modest chronic up regulation of ISGs in PI fetuses and calves reflects a stimulated innate immune response during persistent BVDV nfection. We hypothesized that establishing persistent fetal BVDV infection is also accompanied by the induction of IFN-gamma (IFN-'). The aims of the present study were to determine IFN-' concentration in blood and amniotic fluid from control, TI and PI fetuses during BVDV infection and analyze induction of the IFN-' downstream pathways in fetal lymphoid tissues. Two experiments with in vivo BVDV infectionsw ere 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 66 were collected by Cesarean section on day 190. In Experiment 2, fetuses were collected on days 67 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-' secretion during acute infection both in TI and PI fetuses and that lymphoid tissues such as spleen, liver and thymus, serve both as possible sources of IFN-' and target organs for its effects. Notably, IFN-' induction 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.