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ABSTRACTFrancisella tularensisis a Gram-negative bacterium and the causative agent of the disease tularemia. Escape of F. tularensisfrom the phagosome into the cytosol of the macrophage triggers the activation of the AIM2 inflammasome through a mechanism that is not well understood. Activation of the AIM2 inflammasome results in autocatalytic cleavage of caspase-1, resulting in the processing and secretion of interleukin-1ß (IL-1ß) and IL-18, which play a crucial role in innate immune responses to F. tularensis. We have identified the 5-formyltetrahydrofolate cycloligasegene (FTL_0724) as being important for F. tularensislive vaccine strain (LVS) virulence. Infection of mice in vivowith a F. tularensisLVS FTL_0724mutant resulted in diminished mortality compared to infection of mice with wild-type LVS. The FTL_0724mutant also induced increased inflammasome-dependent IL-1ß and IL-18 secretion and cytotoxicity in macrophages in vitro. In contrast, infection of macrophages with a F. tularensisLVS rluD pseudouridine synthase(FTL_0699) mutant resulted in diminished IL-1ß and IL-18 secretion from macrophages in vitrocompared to infection of macrophages with wild-type LVS. In addition, the FTL_0699mutant was not attenuated in vivo. These findings further illustrate that F. tularensisLVS possesses numerous genes that influence its ability to activate the inflammasome, which is a key host strategy to control infection with this pathogen in vivo.