Abstract

Bovine Viral Diarrhea Virus (BVDV) is the causative agent of multiple diseases: mucosal disease, reproductive failure, infections persistent and bovine immunosuppression; causing several economic losses in the livestock industry. BVDV in vitro induces decrease of important molecules for antiviral defense mechanism, such as proinflammatory cytokines (IL-8, IL-1β, among others). Cytokine production for immunological process is tightly regulated at transcriptional and posttranscriptional levels. Particularly, the transcription factor NF-қB controls the expression of immune and anti- apoptotic genes important for maintain immune homeostasis in the cell through the participation of molecules such as immediate early response 3 (IER3) and A20 (TNFAIP3), both key negative regulators of the immune response. Although IER3 and A20 has been identified in mammals, relatively little is known about the composition of these regulators in other classes of vertebrates, particularly for bovines. We report the first evidence of A20 and IER3 effective negative regulators of NF-κB activity in bovine cells. In addition, our results prompt to bovine A20 and IER3 expression is mediated by BVDV-1. In this context, A20 evidenced the strongest fold increase in expression with virus exposure, a phenomenon blocked by a pharmacological NF-κB inhibitor. Also, it was found that BVDV infection can modify the NF-κB – related early immunity gene expression through IER3 and A20 modulation. This is the first report to find BVDV-1 modulating the activation of A20 and IER3 factors, being possible mechanisms of NF-KB pathway regulation that contributes to immunosuppression induced by BVDV and elucidate potential signaling mechanisms related to pathogen infection in cattle.