Innate and adaptive immune responses to in utero infection with bovine viral diarrhea virus

2015 ◽  
Vol 16 (1) ◽  
pp. 15-26 ◽  
Author(s):  
Thomas R. Hansen ◽  
Natalia P. Smirnova ◽  
Brett T. Webb ◽  
Helle Bielefeldt-Ohmann ◽  
Randy E. Sacco ◽  
...  
Keyword(s):  
Immune Responses ◽  
Bovine Viral Diarrhea ◽  
Type I ◽  
Adaptive Immune Responses ◽  
Diarrhea Virus ◽  
Viral Diarrhea ◽  
Adaptive Immune ◽  
Fetal Infection ◽  
Ifn Γ ◽  
Viral Diarrhea Virus

AbstractInfection of pregnant cows with noncytopathic (ncp) bovine viral diarrhea virus (BVDV) induces rapid innate and adaptive immune responses, resulting in clearance of the virus in less than 3 weeks. Seven to 14 days after inoculation of the cow, ncpBVDV crosses the placenta and induces a fetal viremia. Establishment of persistent infection with ncpBVDV in the fetus has been attributed to the inability to mount an immune response before 90–150 days of gestational age. The result is ‘immune tolerance’, persistent viral replication and shedding of ncpBVDV. In contrast, we describe the chronic upregulation of fetal Type I interferon (IFN) pathway genes and the induction of IFN-γ pathways in fetuses of cows infected on day 75 of gestation. Persistently infected (PI) fetal IFN-γ concentrations also increased at day 97 at the peak of fetal viremia and IFN-γ mRNA was significantly elevated in fetal thymus, liver and spleen 14–22 days post maternal inoculation. PI fetuses respond to ncpBVDV infection through induction of Type I IFN and IFN-γ activated genes leading to a reduction in ncpBVDV titer. We hypothesize that fetal infection with BVDV persists because of impaired induction of IFN-γ in the face of activated Type I IFN responses. Clarification of the mechanisms involved in the IFN-associated pathways during BVDV fetal infection may lead to better detection methods, antiviral compounds and selection of genetically resistant breeding animals.

Attenuated lymphocyte activation leads to the development of immunotolerance in bovine fetuses persistently infected with bovine viral diarrhea virus†

2020 ◽  
Vol 103 (3) ◽  
pp. 560-571 ◽  
Author(s):  
Hanah M Georges ◽  
Katie J Knapek ◽  
Helle Bielefeldt-Ohmann ◽  
Hana Van Campen ◽  
Thomas R Hansen
Keyword(s):  
Immune System ◽  
Bovine Viral Diarrhea Virus ◽  
Lymphocyte Activation ◽  
Control Measures ◽  
Bovine Viral Diarrhea ◽  
Type I ◽  
Persistently Infected ◽  
Diarrhea Virus ◽  
Viral Diarrhea ◽  
Viral Diarrhea Virus

Abstract Bovine viral diarrhea virus continues to cost the cattle industry millions of dollars each year despite control measures. The primary reservoirs for bovine viral diarrhea virus are persistently infected animals, which are infected in utero and shed the virus throughout their lifetime. The difficulty in controlling the virus stems from a limited understanding of transplacental transmission and fetal development of immunotolerance. In this study, pregnant bovine viral diarrhea virus naïve heifers were inoculated with bovine viral diarrhea virus on day 75 of gestation and fetal spleens were collected on gestational days 82, 97, 190, and 245. Microarray analysis on splenic RNA from days 82 and 97 revealed an increase in signaling for the innate immune system and antigen presentation to T cells in day 97 persistently infected fetuses compared to controls. Reverse transcription quantitative polymerase chain reaction on select targets validated the microarray revealing a downregulation of type I interferons and lymphocyte markers in day 190 persistently infected fetuses compared to controls. Protein was visualized using western blot and tissue sections were analyzed with hematoxylin and eosin staining and immunohistochemistry. Data collected indicate that fetal immunotolerance to bovine viral diarrhea virus developed between days 97 and 190, with mass attenuation of the immune system on day 190 of gestation. Furthermore, lymphocyte transcripts were initially unchanged then downregulated, suggesting that immunotolerance to the virus stems from a blockage in lymphocyte activation and hence an inability to clear the virus. The identification of lymphocyte derived immunotolerance will aid in the development of preventative and viral control measures to implement before or during pregnancy.

scholarly journals Persistent fetal infection with bovine viral diarrhea virus differentially affects maternal blood cell signal transduction pathways

2009 ◽  
Vol 36 (3) ◽  
pp. 129-139 ◽  
Author(s):  
Natalia P. Smirnova ◽  
Andrey A. Ptitsyn ◽  
Kathleen J. Austin ◽  
Helle Bielefeldt-Ohmann ◽  
Hana Van Campen ◽  
...  
Keyword(s):  
Immune Response ◽  
Fetal Development ◽  
Blood Cells ◽  
Maternal Blood ◽  
Signal Transduction Pathways ◽  
Bovine Viral Diarrhea ◽  
Type I ◽  
Diarrhea Virus ◽  
Viral Diarrhea ◽  
Viral Diarrhea Virus

The consequences of viral infection during pregnancy include impact on fetal and maternal immune responses and on fetal development. Transplacental infection in cattle with noncytopathic bovine viral diarrhea virus (ncpBVDV) during early gestation results in persistently infected (PI) fetuses with life-long viremia and susceptibility to infections. Infection of the fetus during the third trimester or after birth leads to a transient infection cleared by a competent immune system. We hypothesized that ncpBVDV infection and presence of an infected fetus would alter immune response and lead to downregulation of proinflammatory processes in pregnant dams. Naïve pregnant heifers were challenged with ncpBVDV2 on day 75 (PI fetus) and day 175 [transiently infected (TI) fetus] or kept uninfected (healthy control fetus). Maternal blood samples were collected up to day 190 of gestation. Genome-wide microarray analysis of gene expression in maternal peripheral white blood cells, performed on days 160 and 190 of gestation, revealed multiple signal transduction pathways affected by ncpBVDV infection. Acute infection and presence of a TI fetus caused upregulation of the type I interferon (IFN) pathway genes, including dsRNA sensors and IFN-stimulated genes. The presence of a PI fetus caused prolonged downregulation of chemokine receptor 4 (CXCR4) and T cell receptor (TCR) signaling in maternal blood cells. We conclude that: 1) infection with ncpBVDV induces a vigorous type I IFN response, and 2) presence of a PI fetus causes downregulation of important signaling pathways in the blood of the dam, which could have deleterious consequences on fetal development and the immune response.

scholarly journals Fetal Lymphoid Organ Immune Responses to Transient and Persistent Infection with Bovine Viral Diarrhea Virus

Viruses ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 816 ◽  
Author(s):  
Katie J. Knapek ◽  
Hanah M. Georges ◽  
Hana Van Campen ◽  
Jeanette V. Bishop ◽  
Helle Bielefeldt-Ohmann ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Innate Immune Response ◽  
Adaptive Immune Response ◽  
Innate Immune ◽  
Bovine Viral Diarrhea ◽  
Diarrhea Virus ◽  
Viral Diarrhea ◽  
Adaptive Immune ◽  
Viral Diarrhea Virus

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.

scholarly journals Effects of Delayed or Prolonged Fixation on Immunohistochemical Detection of Bovine Viral Diarrhea Virus Type I in Skin of Two Persistently Infected Calves

2005 ◽  
Vol 17 (5) ◽  
pp. 461-463 ◽  
Author(s):  
Margaret A. Miller ◽  
José A. Ramos-Vara ◽  
Steven B. Kleiboeker ◽  
Robert L. Larson
Keyword(s):  
Bovine Viral Diarrhea Virus ◽  
Immunohistochemical Staining ◽  
Formalin Fixation ◽  
Bovine Viral Diarrhea ◽  
Type I ◽  
Immunohistochemical Detection ◽  
Persistently Infected ◽  
Diarrhea Virus ◽  
Viral Diarrhea ◽  
Viral Diarrhea Virus

The effects of delayed or prolonged fixation on immunohistochemical detection of bovine viral diarrhea virus (BVDV) antigen were evaluated in skin. Ear-notch specimens from 2 calves persistently infected with BVDV type 1 were handled in 1 of 3 ways: 1) fixed in formalin promptly and processed for immunohistochemistry (IHC) after 3–176 days; 2) held at 3–4°C in plastic bags up to 10 days, then fixed in formalin for 2–5 days before processing; or 3) exposed to room air and temperature for 1–5 days before formalin fixation. Immunohistochemical staining intensity was evaluated without the knowledge of specimen handling. Staining of specimens that had been promptly fixed in formalin was moderate to strong at all fixation periods through 36 days, weak or no staining was evident in specimens fixed for 176 days. Refrigerated specimens typically had moderate to strong immunohistochemical staining. Even after 10 days of refrigeration before fixation, all immunohistochemical reactions were positive. However, no immunohistochemical staining was detected in any specimen that was exposed to room air. Results indicate that prompt formalin fixation is optimal for BVDV IHC. Samples can be held in formalin at least 36 days, without loss of reactivity. A 1-day delay in fixation caused no loss of reactivity, provided the specimen was refrigerated and protected from desiccation.

scholarly journals Priming with DNA encoding E2 and boosting with E2 protein formulated with CpG oligodeoxynucleotides induces strong immune responses and protection from Bovine viral diarrhea virus in cattle

2006 ◽  
Vol 87 (10) ◽  
pp. 2971-2982 ◽  
Author(s):  
Rong Liang ◽  
Jan V. van den Hurk ◽  
Lorne A. Babiuk ◽  
Sylvia van Drunen Littel-van den Hurk
Keyword(s):  
Immune Responses ◽  
Bovine Viral Diarrhea Virus ◽  
Bovine Viral Diarrhea ◽  
E2 Protein ◽  
Diarrhea Virus ◽  
Viral Diarrhea ◽  
Boost Vaccination ◽  
Viral Excretion ◽  
Protein Boost ◽  
Viral Diarrhea Virus

The objective of this study was to develop an optimal vaccination strategy for Bovine viral diarrhea virus (BVDV). The E2 protein of BVDV plays a major protective role against BVDV infection. In order to be able to compare DNA, protein and DNA prime–protein boost regimens, a plasmid was constructed encoding a secreted form of the NADL strain E2 protein (pMASIA-tPAsΔE2). Furthermore, a pure secreted recombinant ΔE2 (rΔE2) protein was produced. The rΔE2 protein was formulated with a combination of Emulsigen and CpG oligodeoxynucleotide. Groups of calves were immunized with pMASIA-tPAsΔE2 or with rΔE2, or first with pMASIA-tPAsΔE2 and then with rΔE2. To evaluate the protection against BVDV, calves were challenged with BVDV strain NY-1 after the last immunization. Although all immunized calves developed humoral and cellular immune responses, the antibody responses in the DNA prime–protein boost group were stronger than those elicited by either the DNA vaccine or the protein vaccine. In particular, E2-specific antibody titres were enhanced significantly after boosting the ΔE2 DNA-primed calves with rΔE2 protein. Moreover, protection against BVDV challenge was obtained in the calves treated with the DNA prime–protein boost vaccination regimen, as shown by a significant reduction in weight loss, viral excretion and lymphopenia, compared with the unvaccinated calves and the animals immunized with the DNA or protein only. These results demonstrate the advantage of a DNA prime–protein boost vaccination approach in an outbred species.

scholarly journals Bovine Viral Diarrhea Virus: Prevention of Persistent Fetal Infection by a Combination of Two Mutations Affecting Erns RNase and Npro Protease

2007 ◽  
Vol 81 (7) ◽  
pp. 3327-3338 ◽  
Author(s):  
Gregor Meyers ◽  
Andreas Ege ◽  
Christiane Fetzer ◽  
Martina von Freyburg ◽  
Knut Elbers ◽  
...  
Keyword(s):  
Double Mutant ◽  
Wild Type Virus ◽  
Bovine Viral Diarrhea ◽  
Type Virus ◽  
Wild Type ◽  
Diarrhea Virus ◽  
Viral Diarrhea ◽  
Fetal Infection ◽  
Fetal Serum ◽  
Viral Diarrhea Virus

ABSTRACT Different genetically engineered mutants of bovine viral diarrhea virus (BVDV) were analyzed for the ability to establish infection in the fetuses of pregnant heifers. The virus mutants exhibited either a deletion of the overwhelming part of the genomic region coding for the N-terminal protease Npro, a deletion of codon 349, which abrogates the RNase activity of the structural glycoprotein Erns, or a combination of both mutations. Two months after infection of pregnant cattle with wild-type virus or either of the single mutants, the majority of the fetuses contained virus or were aborted or found dead in the uterus. In contrast, the double mutant was not recovered from fetal tissues after a similar challenge, and no dead fetuses were found. This result was verified with a nonrelated BVDV containing similar mutations. After intrauterine challenge with wild-type virus, mutated viruses, and cytopathogenic BVDV, all viruses could be detected in fetal tissue after 5, 7, and 14 days. Type 1 interferon (IFN) could be detected in fetal serum after challenge, except with wild-type noncytopathogenic BVDV. On days 7 and 14 after challenge, the largest quantities of IFN in fetal serum were induced by the Npro and RNase-negative double mutant virus. The longer duration of fetal infection with the double mutant resulted in abortion. Therefore, for the first time, we have demonstrated the essential role of both Npro and Erns RNase in blocking interferon induction and establishing persistent infection by a pestivirus in the natural host.

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