Respiratory syncytial virus-induced high mobility group box 1 secretion modulates innate immune response to promote inflammation

Abstract

Abstract Respiratory syncytial virus (RSV) is the single most common human pathogen responsible for ~ 60% of all acute lower respiratory tract infections in young children, and is a major cause of severe respiratory morbidity and mortality in the elderly, and the immunocompromised. Yet, no vaccine or efficacious treatment is available. Although the mechanisms of RSV-induced acute airway disease are not fully understood, lung inflammatory and immune events are key. Our studies show that RSV induces increased extracellular secretion of high-mobility group box 1 (HMGB1), a prominent damage-associated molecular pattern family member that alerts the immune system to potential damage and trigger immediate response. The goal of this study is to investigate the molecular mechanisms of RSV-induced HMGB1 release in the activation of innate immune response in promoting lung inflammation. Studies were conducted in BALB/c mice as well as human lung epithelial cells including A549 and normal small alveolar epithelial cells. To determine the role of HMGB1 in the activation of innate immune signaling, BALB/c mice and airway epithelial cells were infected with RSV in the presence or absence of recombinant HMGB1 or HMGB1 monoclonal antibody and measured RIG-I-dependent interferon-mediated innate antiviral immune response. Our studies demonstrated an important role of HMGB1 in cellular protection and the activation of innate immune signaling cascades to promote inflammation. Our studies indicate that HMGB1 acts as a signaling molecule to induce an increased inflammatory response in the lung, thus contributing to RSV pathogenesis. Modulation of proinflammatory function of HMGB1 may attenuate RSV-induced lung inflammation.