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.

Pyruvate is a key metabolite for energy synthesis. After the production of pyruvate through glycolysis, the molecule is shuttled into the mitochondria. Once there, it is modified for use in the TCA cycle and the energy derived from pyruvate is eventually converted into ATP. While pyruvate is a key metabolite, it also appears to have anti-inflammatory properties. In models of sterile inflammation, like ischemia, pyruvate limits inflammation. We observed that infecting murine bone marrow derived macrophages (BMDM) with influenza A virus (IAV) and treating those macrophages with sodium pyruvate results in lower inflammasome activation and reactive oxygen species (ROS) production. However, this was specific to IAV infection as inflammasome activation and ROS were not affected by sodium pyruvate during E. coli infection or lipopolysaccharide (LPS) and ATP treatment of BMDMs. Our results show that IAV induces a potent and unique metabolic reprograming of infected cells. The addition of sodium pyruvate facilitates ATP production, which correlates with less mitochondrial damage and reduced inflammasome activation. Thus, pyruvate deserves additional examination as an anti-inflammatory treatment in diseases where mitochondrial metabolic stress is a factor.