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Type 2 Bovine Viral Diarrhea Virus Npro Suppresses Type I Inteferon Pathway Signaling in Bovine Cells and Augments Bovine Respiratory Syncytal Virus Replication

Abdulrahman Abdulaziz A Alkheraif, University of Nebraska - Lincoln


Bovine viral diarrhea virus (BVDV) and bovine respiratory syncytial virus (BRSV) infections contribute to the bovine respiratory disease complex (BRDC), which is a multi-factorial disorder involving co-infections of viruses and bacteria including mycoplasma. BRDC causes great economic losses to the United States feedlot industry. BVDV infection induces immunosuppression in infected animals. BVDV Npro binds and degrades the transcription factor interferon regulatory factor-3 (IRF-3) and effectively blocks type I interferon (type I IFN) expression in host cells. BRSV nonstructural proteins, NS1 and NS2, block activation of IRF-3. In calves, concurrent infection with BVDV and BRSV resulted in more severe clinical signs of disease and extensive lung lesions than infection with either virus alone. The objective of this study was to extend the understanding of the role of the Npro of noncytopathic BVDV-2 (pestivirus B) on type I IFN pathway signaling in bovine turbinate (BT) cells during single and co-infection with BRSV. Based on real-time quantitative-reverse transcription-polymerase chain reaction, the BVDV-2 mutant with dysfunctional Npro (BVDV2-E) significantly up-regulated protein kinase R (PKR), TANK-Binding Kinase 1, IRF-3, IRF-7, and interferon-β (IFN-β) mRNAs compared to BVDV-2 wild-type (BVDV2-wt) and BRSV in single and co-infected BT cells. BRSV-infected cells expressed significantly up-regulated PKR, IRF-3, IRF-7, and IFN-β mRNAs, whereas BVDV2-wt, but not BVDV2-E, abolished this up-regulation in co-infection. No significant differences were observed in mitochondrial antiviral signaling, Nuclear Factor-κB (NF-κB), and NIMA-Interacting 1 mRNAs. A dual-luciferase reporter assay showed that BVDV2-wt significantly increased NF-κB activity compared to BVDV2-E, while BVDV2-E significantly increased IFN-β activity compared to BVDV2-wt. BT cells infected with BVDV2-E produced more IRF-3 protein compared to cells infected with BRSV or BVDV2-wt. The BRSV titer and RNA levels significantly increased in cells co-infected with BRSV/BVDV2-wt compared to cells co-infected with BRSV/BVDV2-E or infected with BRSV alone. BVDV2-E single and co-infected cells synthesized type I IFN significantly higher than BVDV2-wt single and co-infected BT cells. These findings are useful in defining the role of the intact BVDV-2 Npro on type I IFN pathway signaling and support the understanding of the mechanism underlying the synergistic action of BVDV2-wt and BRSV inhibition of type I IFN. The inhibition of BRSV-induced signals by BVDV augments BRSV infection.

Subject Area

Biomedical engineering|Veterinary services

Recommended Citation

Alkheraif, Abdulrahman Abdulaziz A, "Type 2 Bovine Viral Diarrhea Virus Npro Suppresses Type I Inteferon Pathway Signaling in Bovine Cells and Augments Bovine Respiratory Syncytal Virus Replication" (2018). ETD collection for University of Nebraska-Lincoln. AAI10845327.