Francisella tularensis (Ft) is the causative agent of tularemia. Macrophages are a major reservoir of Ft in vivo. After uptake, Ft escapes the phagosome and replicates in the macrophage cytosol. Our long-term goal is to elucidate the molecular mechanisms by which Ft evades elimination by the innate immune response. We have been able to show that Ft inhibits phagosome maturation at an early stage. Moreover, we have identified protein kinase C? (PKc?) as the first host factor known to be inhibited by Ft to prevent phagosome-lysosome fusion. Elucidating the mechanism by which PKC? activity is disrupted is a goal of this study. Concurrently, are identifying novel Ft virulence factors using reverse genetic screening technologies. Mutants identified in these screens will be characterized in detail using primary human macrophages and a mouse intranasal infection model.