Theme 2 : Redox regulation of the antiviral response

 

The mucosal linings of the airways are constantly exposed to an array of microbial pathogens, including life-threatening respiratory viruses. Control of the host-microbe homeostasis at the mucosal epithelia is essential to prevent microorganisms-triggered inflammatory diseases. More than just a physicochemical barrier, airway epithelial cells (AEC) are now well documented to play a key role in the early elements of the innate host response to virus infection. AEC rapidly recognize invading respiratory viruses to actively trigger the production of antiviral substances, including mucus, peptides and cytokines (mainly type I and III Interferons) that limit invasion and spread of the pathogen. Additionally, AEC secrete a panel of proinflammatory cytokines and chemokines that recruit and activate immune cells to the site of infection. There is good evidence for a critical role of reactive oxygen species (ROS) in the pathogenesis of acute and chronic lung inflammatory diseases, such as acute lung injury or chronic obstructive pulmonary disease. On the other hand, we and others have highlighted the role of ROS, such as superoxide and hydrogen peroxide, as second messengers in signal transduction pathways modulating antiviral and proinflammatory cytokine gene expression in virus-infected AEC. Our research endeavor of the past years allowed us to firmly establish that ROS generated by NOX2 and DUOX2 NADPH oxidases modulate the initiation and duration of the IFN response. Our current work is aimed at deciphering the molecular mechanisms by which NOX2 and DUOX2 control the antiviral signaling cascades. Moreover, our recent work has highlighted the requirement of cytokines (IFN-I and TNFa) synergism to induce DUOX2 in AEC through a novel STAT2/IRF9 pathway. Further characterization of this novel antiviral pathway is currently underway. Use of antioxidants or other pharmacological agents to modulate the oxidative stress have started to be considered as potential therapeutic strategy in a number of diseases, including acute and chronic lung diseases. Therefore, our research is also relevant to other lung pathologies that can be exacerbated by virus infections.