The role of high-mobility group box 1 protein in respiratory syncytial virus-induced autophagy

Abstract

Abstract Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory tract infections in infants and young children worldwide, for which no efficacious treatments or vaccines are currently available. Although the pathogenic mechanisms of RSV-induced acute airway disease are still unclear, lung immune and inflammatory responses are key. High-mobility group box 1 (HMGB1) is a redox-sensitive multifunctional protein that serves as both a DNA regulatory protein and an extracellular signaling molecule that mediates the activation of inflammatory responses to infection/injury. HMGB1 has been implicated in mitochondrial function and quality control. The objective of this study is to investigate the role of HMGB1 in autophagosome formation and mitochondrial quality control in RSV infection. Studies were conducted in lung epithelial cells including A549 and normal small alveolar epithelial cells. Our studies show that RSV induces HMGB1 secretion in lung epithelial cells via NFκB and TLR4 pathways, and activates innate immune cells to promote inflammation. We show that RSV-induces LC3B and promote autophagy whereas recombinant HMGB1 (rHMGB1) treatment inhibits RSV-induced autophagy. We also show that RSV infection inhibits the inflammasome pathway in lung epithelial cells but rHMGB1 treatment activates inflammasomes. Our results indicate that RSV-induced epithelial HMGB1 secretion triggers inflammasome activation in innate immune cells to promote inflammation. Understanding HMGB1 and associated cellular signaling in RSV-induced lung inflammation may pave the way for the development of novel therapeutic interventions to treat not only RSV, but also other respiratory infections that affect humans of all ages.