Francisella tularensis is the etiologic agent of tularemia, a zoonotic disease maintained in the environment by rodents, lagamorphs and their ectoparasites. The low infectious dose, the high mortality rate associated with pneumonic disease and the potential to genetically engineer F. tularensis have prompted increased efforts to identify critical targets for therapeutics or vaccines. New genetic approaches and tools have been developed for Francisella, allowing rapid progress in understanding some of the biological outcomes occurring during infections both in tissue culture and in animal model systems. This application proposes to develop the first tick-mouse model of Francisella infection and to study transmission, tissue localization and define the changes in bacterial burden during different stages of tick development. The skill sets of two laboratories are focused on these major goals. Dr. Coburn brings her experience in the analysis of tick-borne Borrelia infections and Dr. Frank contributes her expertise in the genetics and pathogenesis of types A and B F. tularensis to the project. Tick-borne F. tularensis is a major mode of transmission to humans, yet little is known about the acquisition, maintenance or replication of the bacteria in these arthropod vectors. To address this critical knowledge gap, we will establish the first well-defined tick-mouse infection model system using the non-select agent F. tularensis strain LVS. Overall, we propose to fill an important gap in our understanding of tick/F. tularensis biology and pave the way for future work using genetic approaches to identify important components of the bacterium that mediate maintenance in the tick and transmission to mammalian hosts. These bacterial components may serve as novel targets for therapeutic or vaccine interventions.