Mechanisms Regulating IL-1β Mediated Inflammation during Secondary Bacterial Pneumonia

Abstract Viral bacterial coinfections are known to cause severe pneumonia due to enhanced pathogen growth and excessive or altered immune responses. Despite knowing the overall causes for disease severity, current treatments fail to improve disease in many patients. Thus, an improved understanding of the specific immune pathways involved is needed to improve therapeutic treatment design. Interlukine-1β (IL-1β) is an important immune signaling cytokine responsible for inflammation. It exists as an inactive precursor that can be activated by caspase-1 containing inflammasomes. We found that coinfection of Influenza A virus and Streptococcus pneumoniae results in inflammasome activation mainly through the NOD-like receptor protein NLRP3. IL-1β levels are synergistically enhanced during coinfection, but not overall inflammasome activation. Instead, enhanced activation of the transcription factor NF-κB results in increased production of pro-IL-1β, which is subsequently processed into its active form by the inflammasome. In vivo, we discovered that IL-1β regulates lung pathology, and mice treated with a combination of antibiotics and IL-1β neutralizing antibodies have improved weight loss and mortality compared to either treatment individually.