AttenuatedFrancisella novicidaTransposon Mutants Protect Mice against Wild-Type Challenge

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Abstract
Francisella tularensisis the bacterial pathogen that causes tularemia in humans and a number of animals. To date, there is no approved vaccine for this widespread and life-threatening disease. The goal of this study was to identifyF. tularensismutants that can be used in the development of a live attenuated vaccine. We screenedF. novicidatransposon mutants to identify mutants that exhibited reduced growth in mouse macrophages, as these cells are the preferred host cells ofFrancisellaand an essential component of the innate immune system. This approach yielded 16F. novicidamutants that were 100-fold more attenuated for virulence in a mouse model than the wild-type parental strain. These mutants were then tested to determine their abilities to protect mice against challenge with high doses of wild-type bacteria. Five of the 16 attenuated mutants (with mutations corresponding todsbB, FTT0742,pdpB,fumA, andcarBin theF. tularensisSCHU S4 strain) provided mice with protection against challenge with high doses (>8 × 105CFU) of wild-typeF. novicida. We believe that these findings will be of use in the design of a vaccine against tularemia.

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