Effect of tobacco smoke on respiratory syncytial virus-induced high-mobility group box 1-mediated innate antiviral signaling

Abstract

Abstract Exposure to tobacco smoke (TS), either direct or secondhand, is associated with an increase in the severity of lower respiratory tract infections, including bronchiolitis, mainly caused by respiratory syncytial virus (RSV). No vaccine or effective treatment is available for RSV. Although the mechanism of TS-induced RSV severity remains largely unknown, lung immune responses are key. High Mobility Group Box-1 (HMGB1) is a multifunctional nuclear protein that is released to the extracellular space during infection and regulates inflammatory responses as damage-associated molecular pattern. The goal of this study is to dissect the role of HMGB1 in the activation of antiviral signaling in RSV and TS-induced airway inflammation. Studies were conducted in airway epithelial cells, including A549 and normal small alveolar epithelial cells. We show that RSV and TS-induced oxidative stress post-translationally modifies HMGB1 including hyperacetylation, phosphorylation, and oxidation, leading to its enhanced extracellular secretion from lung epithelial cells. Secreted HMGB1 activates signaling cascades to activate p38 MAPK and NF-κB to induce proinflammatory mediator release from immune cells and induce inflammation. We also show that hmgb1 knockdown exacerbates inflammation in RSV-infected and TS-exposed cells and that treatment with recombinant HMGB1 activates immune cells to induce an inflammatory response, promotes the activation of antiviral pathways and inhibits viral replication. Our studies suggest an important role for HMGB1 in TS-induced RSV pathogenesis and guide the development of novel therapeutic strategies against respiratory infections that are caused or exacerbated by environmental toxicants such as TS.