Fetal Lymphoid Organ Immune Responses to Transient and Persistent Infection with Bovine 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.

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DDIT3 targets innate immunity via the DDIT3-OTUD1-MAVS pathway to promote BVDV replication

Journal of Virology ◽

10.1128/jvi.02351-20 ◽

2020 ◽

Author(s):

Song Wang ◽

Peili Hou ◽

Wei Pan ◽

Wenqi He ◽

Daniel Chang He ◽

...

Keyword(s):

Immune Response ◽

Innate Immunity ◽

Innate Immune Response ◽

Innate Immune ◽

Bovine Viral Diarrhea ◽

Bovine Kidney ◽

Diarrhea Virus ◽

Viral Diarrhea ◽

Mdbk Cells ◽

Viral Diarrhea Virus

DNA damage inducible transcript 3 (DDIT3) plays important roles in ER stress-induced apoptosis and autophagy, but its role in innate immunity is not clear. Here, we report that DDIT3 inhibits the antiviral immune response during bovine viral diarrhea virus (BVDV) infection by targeting mitochondrial antiviral signaling (MAVS) in Madin-Darby bovine kidney (MDBK) cells and in mice. BVDV infection induced high DDIT3 mRNA and protein expression. DDIT3 overexpression inhibited type I interferon (IFN-I) and IFN-stimulated gene production, thereby promoting BVDV replication, while DDIT3 knockdown promoted the antiviral innate immune response to suppress viral replication. DDIT3 promoted NF-κB-dependent OTU deubiquitinase 1 (OTUD1) expression. Furthermore, OTUD1 induced upregulation of the E3 ubiquitin ligase Smurf1 by deubiquitinating Smurf1, and Smurf1 degraded MAVS in MDBK cells in a ubiquitination-dependent manner, ultimately inhibiting IFN-I production. Moreover, knocking out DDIT3 promoted the antiviral innate immune response to reduce BVDV replication and pathological changes in mice. These findings provide direct insights into the molecular mechanisms by which DDIT3 inhibits IFN-I production by regulating MAVS degradation. IMPORTANCE Extensive studies have demonstrated roles of DDIT3 in apoptosis and autophagy during viral infection. However, the role of DDIT3 in innate immunity remains largely unknown. Here, we show that DDIT3 was positively regulated in bovine viral diarrhea virus (BVDV)-infected Madin-Darby bovine kidney (MDBK) cells and could significantly enhance BVDV replication. Importantly, DDIT3 induced OTU deubiquitinase 1 (OTUD1) expression by activating the NF-κB signaling pathway, thus increasing intracellular Smurf1 protein levels to degrade MAVS and inhibit IFN-I production during BVDV infection. Together, these results indicate that DDIT3 plays critical roles in host innate immunity repression and viral infection facilitation.

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Innate Immune Responses of Calves during Transient Infection with a Noncytopathic Strain of Bovine Viral Diarrhea Virus

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.11.2.302-312.2004 ◽

2004 ◽

Vol 11 (2) ◽

pp. 302-312 ◽

Cited By ~ 30

Author(s):

Doris Müller-Doblies ◽

Adrian Arquint ◽

Patrick Schaller ◽

Peter M. H. Heegaard ◽

Monika Hilbe ◽

...

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Bovine Viral Diarrhea Virus ◽

Innate Immune ◽

Bovine Viral Diarrhea ◽

Diarrhea Virus ◽

Viral Diarrhea ◽

Amyloid A ◽

Mx Protein ◽

Viral Diarrhea Virus

ABSTRACT In this study, six immunocompetent calves were experimentally infected with a noncytopathic strain of bovine viral diarrhea virus (BVDV), and the effects of the viral infection on parameters of the innate immune response of the host were analyzed. Clinical and virological data were compared with the temporal activation of the alpha/beta interferon-regulated Mx gene in white blood cells (WBC) and skin as well as the upregulation of the acute-phase serum proteins haptoglobin (Hp) and serum amyloid A (SAA). The viral strain used did provoke transient health impairment, namely, fever and leukopenia that were associated with viremia, viral shedding with nasal secretions, and antiviral seroconversion. Complete recovery was observed within 3 weeks. Elevated levels of SAA and Hp were apparent from days 4 to 13 and 8 to 11, respectively. In WBC, the levels of Mx mRNA and Mx protein were elevated from days 2 to 15. In the context of this study with BVDV, the level of Mx protein expression in WBC provided the most telling diagnostic window to monitor the host's ongoing innate immune response.

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END-phenomenon negative bovine viral diarrhea virus that induces the host's innate immune response supports propagation of BVDVs with different immunological properties

Virology ◽

10.1016/j.virol.2019.09.016 ◽

2019 ◽

Vol 538 ◽

pp. 97-110 ◽

Cited By ~ 1

Author(s):

Mai Shiokawa ◽

Tsutomu Omatsu ◽

Yukie Katayama ◽

Kaoru Nishine ◽

Yuri Fujimoto ◽

...

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Bovine Viral Diarrhea Virus ◽

Innate Immune ◽

Bovine Viral Diarrhea ◽

Immunological Properties ◽

Diarrhea Virus ◽

Viral Diarrhea ◽

Viral Diarrhea Virus

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Plant Phenolics and Lectins as Vaccine Adjuvants

Current Pharmaceutical Biotechnology ◽

10.2174/1389201020666190716110705 ◽

2019 ◽

Vol 20 (15) ◽

pp. 1236-1243 ◽

Cited By ~ 2

Author(s):

Hernández-Ramos Reyna-Margarita ◽

Castillo-Maldonado Irais ◽

Rivera-Guillén Mario-Alberto ◽

Ramírez-Moreno Agustina ◽

Serrano-Gallardo Luis-Benjamín ◽

...

Keyword(s):

Immune Response ◽

Immune System ◽

Innate Immune Response ◽

Adaptive Immune Response ◽

The Body ◽

Innate Immune ◽

Vaccine Adjuvants ◽

Plant Phenolics ◽

Adaptive Immune ◽

Foreign Substance

Background: The immune system is responsible for providing protection to the body against foreign substances. The immune system divides into two types of immune responses to study its mechanisms of protection: 1) Innate and 2) Adaptive. The innate immune response represents the first protective barrier of the organism that also works as a regulator of the adaptive immune response, if evaded the mechanisms of the innate immune response by the foreign substance the adaptive immune response takes action with the consequent antigen neutralization or elimination. The adaptive immune response objective is developing a specific humoral response that consists in the production of soluble proteins known as antibodies capable of specifically recognizing the foreign agent; such protective mechanism is induced artificially through an immunization or vaccination. Unfortunately, the immunogenicity of the antigens is an intrinsic characteristic of the same antigen dependent on several factors. Conclusion: Vaccine adjuvants are chemical substances of very varied structure that seek to improve the immunogenicity of antigens. The main four types of adjuvants under investigation are the following: 1) Oil emulsions with an antigen in solution, 2) Pattern recognition receptors activating molecules, 3) Inflammatory stimulatory molecules or activators of the inflammasome complex, and 4) Cytokines. However, this paper addresses the biological plausibility of two phytochemical compounds as vaccine adjuvants: 5) Lectins, and 6) Plant phenolics whose characteristics, mechanisms of action and disadvantages are addressed. Finally, the immunological usefulness of these molecules is discussed through immunological data to estimate effects of plant phenolics and lectins as vaccine adjuvants, and current studies that have implanted these molecules as vaccine adjuvants, demonstrating the results of this immunization.

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Recombinant E2 glycoprotein of bovine viral diarrhea virus induces a solid humoral neutralizing immune response but fails to confer total protection in cattle

Brazilian Journal of Medical and Biological Research ◽

10.1590/s0100-879x2007000600010 ◽

2007 ◽

Vol 40 (6) ◽

pp. 813-818 ◽

Cited By ~ 7

Author(s):

S. Chimeno Zoth ◽

M.R. Leunda ◽

A. Odeón ◽

O. Taboga

Keyword(s):

Immune Response ◽

Bovine Viral Diarrhea Virus ◽

Bovine Viral Diarrhea ◽

Diarrhea Virus ◽

Viral Diarrhea ◽

E2 Glycoprotein ◽

Viral Diarrhea Virus

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

Biology of Reproduction ◽

10.1093/biolre/ioaa088 ◽

2020 ◽

Vol 103 (3) ◽

pp. 560-571 ◽

Cited By ~ 3

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.

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