Abstract
Bovine Viral Diarrhea Virus (BVDV) fetal infections occur in two forms; persistent infection (PI) or transient infection (TI), depending on what stage of gestation the fetus is infected. Examination of lymphoid organs from both PI and TI fetuses reveals drastically different fetal responses, dependent upon the developmental stage of the fetal immune system. Total RNA was extracted from the thymuses and spleens of uninfected control, PI, and TI fetuses collected on day 190 of gestation to test the hypothesis that BVDV infection impairs the innate and adaptive immune response in the fetal thymus and spleen of both infection types. Transcripts of genes representing the innate immune response and adaptive immune response genes were assayed by Reverse Transcription quatitative PCR (RT-qPCR) (2−ΔΔCq; fold change). Genes of the innate immune response, interferon (IFN) inducible genes, antigen presentation to lymphocytes, and activation of B cells were downregulated in day 190 fetal PI thymuses compared to controls. In contrast, innate immune response genes were upregulated in TI fetal thymuses compared to controls and tended to be upregulated in TI fetal spleens. Genes associated with the innate immune system were not different in PI fetal spleens; however, adaptive immune system genes were downregulated, indicating that PI fetal BVDV infection has profound inhibitory effects on the expression of genes involved in the innate and adaptive immune response. The downregulation of these genes in lymphocytes and antigen-presenting cells in the developing thymus and spleen may explain the incomplete clearance of BVDV and the persistence of the virus in PI animals while the upregulation of the TI innate immune response indicates a more mature immune system, able to clear the virus.
Highlights
Bovine viral diarrhea viruses (BVDV) cause significant economic losses in all sectors of cattle production worldwide [1,2,3,4]
RNA-activated (PKR), as well as the RNA helicases: DEAD Box Protein 58 (DDX58), known as retinoic acid-inducible gene (RIGI), melanoma differentiation-associated protein 5 (MDA5); and DExH-box helicase 58 (DHX58) were shown to be chronically upregulated in the persistently infected (PI) animal postnatally [31]. These results indicate that PI fetuses and placenta respond to Bovine Viral Diarrhea Virus (BVDV) with an innate immune response, albeit somewhat reduced compared to transient infection (TI) fetuses [28,29,31]
These findings indicate that the fetus responds to ncp BVDV infection with an innate immune response, much like the innate response to ncp BVDV infection in postnatal calves shown by Palomares et al (2013); inhibition of the innate immune response by viral proteins does not entirely explain viral persistence in vivo [32]
Summary
Bovine viral diarrhea viruses (BVDV) cause significant economic losses in all sectors of cattle production worldwide [1,2,3,4]. If maternal infection with ncp BVDV occurs prior to 125 days of gestation, the fetus becomes persistently infected (PI) with the virus and is born without BVDV-specific antibodies [12,13]. BVDV infection of pregnant cows after 150 days of gestation results in a transient infection (TI) of the fetus. These TI calves are born with BVDV-specific antibodies indicative of a functional adaptive immune response and clearance of the virus [9,14,15]. Virus-specific immune responses in the bovine fetus develops between days 125 and 150; BVDV infection during this time may result in either a PI or TI, depending on the individual fetuses [16]. The differences in the outcomes of PI and TI fetal infections have been attributed to the maturation and function of the fetal immune system at the time of infection [17]
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