BRD4 Couples NF-κB/RelA with Airway Inflammation and the IRF-RIG-I Amplification Loop in Respiratory Syncytial Virus Infection

• DOI: 10.1128/jvi.00007-17
• Publication Date: 2017-01-12T02:32:08Z
• Authors: Bing Tian; Jun Yang; Yingxin Zhao; Teodora Ivanciuc; Hong Sun; Roberto P. Garofalo; Allan R. Brasier
• Keywords: BRD4; IRF7

ABSTRACT The airway mucosa expresses protective interferon (IFN) and inflammatory cytokines in response to respiratory syncytial virus (RSV) infection. In this study, we examine the role of bromodomain containing 4 (BRD4) mediating innate immune human small epithelial cells. We observe that RSV induces BRD4 complex with NF-κB/RelA. is functionally required for expression NF-κB-dependent gene regulatory network (GRN), including IFN factor 1 (IRF1) IRF7, which mediate a cross talk pathway RIG-I upregulation. Mechanistically, cyclin-dependent kinase 9 (CDK9) recruitment phospho-Ser 2 carboxy-terminal domain (CTD) RNA polymerase (Pol) II formation on promoters IRF1 , IRF7 producing their enhanced by transcriptional elongation. also find independently regulates CDK9/phospho-Ser CTD Pol IRF3-dependent IFN-stimulated genes (ISGs). vivo poly(I·C)-induced neutrophilia mucosal chemokine production are blocked small-molecule inhibitor. Similarly, inhibition reduces RSV-induced neutrophilia, CXC expression, activation IRF7-RIG-I autoamplification loop, obstruction. infection activates acetyltransferase activity histone H3 Lys (K) 122, demonstrating . These data validate as major effector inflammation disease. coupling NF-κB IRF-RIG-I facilitates antiviral ISG expression. may be strategy reduce exuberant virus-induced inflammation. IMPORTANCE United States, 2.1 million children annually require medical attention infections. A first line defense infected Expression requires elongation factors rapidly induce through an unknown mechanism. discovered (CDK9). stable CDK9 binding, formation, activity. Inhibition blocks Toll-like receptor 3 (TLR3)-dependent inflammation, its importance Our study shows plays central amplification loop vital modulating