| Francisella tularensis is the etiologic agent of the highly infectious animal and human disease tularemia. Francisella tularensis survival is in part dependent on its ability to resist the microbicidal activity of host-generated reactive oxygen and nitrogen species (ROS/RNS). We hypothesize that the antioxidant status of Francisella tularensis plays a critical role in virulence and immune suppression. F. tularensis mutants deficient in either superoxide dismutases (sodB and sodC) or catalase ( katG) were used to examine their role in defense against ROS/RNS-mediated microbicidal activity of infected macrophages. The loss of F. tularensis SODs attenuated intramacrophage survival and virulence in mice, which was reversible by inhibition of superoxide (O2·- ) or nitric oxide (NO). The highly virulent strain, SchuS4, has a robust ROS scavenging capacity. SchuS4 blocked signals required for macrophage cytokine production, including, Akt phosphorylation, IkappaBalpha-degradation, and NF-kappaB nuclear localization and activation. Mutation of katG sensitized F. tularensis to H2O 2, enhanced Akt phosphorylation, NF-kappaB activation and proinflammatory cytokine production. Together, these findings suggest a novel role for bacterial antioxidants in restricting macrophage activation and virulence through their ability to preserve phosphatases that temper kinase signaling and proinflammatory cytokine production. |
