Ataxia Telangiectasia Mutated Kinase Mediates NF-κB Serine 276 Phosphorylation and Interferon Expression via the IRF7-RIG-I Amplification Loop in Paramyxovirus Infection

Abstract

Respiratory syncytial virus (RSV) is Respiratory syncytial virus (RSV), a negative-sense, singlestranded RNA (ssRNA) virus of the Paramyxoviridae family, is one of the most important respiratory pathogens of young children worldwide (1). Epidemiological studies have shown that RSV infects almost all children in the United States by the age of 3, producing primarily upper respiratory tract infections and otitis media (2). In a small subset of immunologically naive or predisposed infants, RSV infection produces a more severe, lower respiratory tract infection (LRTI), an event that accounts for over 3 million hospitalizations and about 200,000 deaths (3, 4). Importantly, there are no effective vaccines or treatments available (2).In seasonal epidemics, RSV is spread via large droplets and self-inoculation (3). Once infected, RSV replicates in the nasal mucosa intraepithelial bridges into the lower respiratory tract or by free virus in respiratory secretions binding to epithelial cilia (5, 6). In the lower airway, RSV replicates primarily in epithelial cells, where it generates bronchial inflammation, epithelial necrosis, sloughing, peribronchial mononuclear cell infiltration, and submucosal edema producing obstructive physiology (7-9). The pathogenesis of LRTI involves an interplay between viral inoculum, host factors, and immune response and is not fully understood (10). Children with bronchiolitis present symptoms at times

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

“…We earlier discovered that the nuclear phosphatidylinositol 3-kinase (PI3 kinase) ataxia telangiectasia mutated (ATM) mediates nuclear ROS signaling in response to RSV infection upstream of RelA Ser 276 phosphorylation by the mitogen and stress kinase (11,59). Additionally, RSV replication induces cellular senescence via ROS and DNA double-strand breaks associated with the ATM-TP53 pathway in a mouse model (60).…”

“…The supernatants were collected and were quantified for protein concentrations. Equal volumes of nuclear lysates were incubated overnight at 4°C with 4 g of IgG or CDK9 Ab in ChIP dilution buffer (11). Immune complexes were collected with 40 l protein A magnetic beads (Dynal Inc.).…”

“…Our recent computational model of the integrated innate response predicted-and experimentally verified-that RIG-I amplification is downstream of an NF-B-IRF cross talk pathway. Here, the reactive oxygen species (ROS)-induced NF-B phosphorylation is required for upregulation of IRF1 and IRF7 transcription factors (10,11). In addition, we previously observed that RSV-activated RelA binds to the IRF7 promoter and is required for IRF7 expression (11); that both RelA and IRF7 bind to the RIG-I promoter, potentiating RIG-I expression (10); and that RIG-I is required for sustained type I IFN expression using siRNA-mediated silencing (30).…”

“…Here, the reactive oxygen species (ROS)-induced NF-B phosphorylation is required for upregulation of IRF1 and IRF7 transcription factors (10,11). In addition, we previously observed that RSV-activated RelA binds to the IRF7 promoter and is required for IRF7 expression (11); that both RelA and IRF7 bind to the RIG-I promoter, potentiating RIG-I expression (10); and that RIG-I is required for sustained type I IFN expression using siRNA-mediated silencing (30). With IFN=s secondary effect on IRF1/7 upregulation, a positive regulatory loop is established, producing an antiviral response (10,11,37).…”

Induction of DNA double-strand breaks and cellular senescence by human respiratory syncytial virus

“…3,25,74 In addition, the infection courses with delayed low levels of apoptosis due to different antiapoptotic (resistance) mechanisms. 12,19,42,49,50 This evidence together with the fact that HRSV is able to activate the DNA damage response (DDR) 21 led us to investigate the role of HRSV in DNA damage and cellular senescence.…”