Intracellular Redox Modulation by Francisella tularensis Perturbs the Activation of the Aim2 Inflammasome 9035

Abstract Description Francisella tularensis (Ft) is a Gram-negative, intracellular bacterium and the causative agent of tularemia, a disease with a 30–60% fatality rate if untreated. Due to its low infectious dose and high mortality, Ft is considered a potential bioterrorism agent. Previous studies demonstrated that Ft suppresses host innate immune responses, including inflammasome-mediated signaling, resulting in reduced cytokine production, innate immune cell recruitment, and bacterial clearance. The absent in melanoma 2 (Aim2) inflammasome, activated by double-stranded DNA, promotes secretion of IL-1β and IL-18, key cytokines required for Ft clearance. However, Ft suppresses Aim2 activation through unknown mechanisms. We hypothesized that Ft modulates the intracellular redox environment to inhibit Aim2 inflammasome activation. Using an Ft mutant deficient in the oxidative stress regulator OxyR (ΔoxyR), we observed elevated IL-1β secretion and Aim2-dependent caspase-1 activation in infected macrophages compared to those infected with the wild-type Ft. Increased expression of IRF1 and GBP2, upstream components of Aim2 signaling, was also detected in ΔoxyR-infected macrophages. These effects were abolished in NADPH oxidase-deficient macrophages, highlighting a role for reactive oxygen species in this pathway. Our findings reveal that OxyR suppresses Aim2 inflammasome activation by regulating redox homeostasis, providing new insights into Ft pathogenesis. Funding Sources This work was funded by NIH/NIAID Grant 1R15AI107698. Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)