The goal of this proposal is to understand the strategies used by F. tularensis to evade the immune response, and to ultimately devise ways to defeat the immune evasion by the bacteria. F. tularensis is a gram-negative, facultative intracellular bacterium. This bacteria require only a very low infective dose via aerosol infection, and has a long lifetime in the environment. Although F. tularensis infection in the US is not highly prevalent, it has the potential to become an important pathogen especially following intentional release. While the immune response to F. tularensis has not been well studied, it does require T cells for clearance of infection and resistance to reinfection. Our preliminary work shows that like many viruses and some bacteria, F. tularensis has evolved multiple strategies for evading the host innate and adaptive immune response. Two of these, the production of PGE2 by infected host cells and the down-regulation of MHC class I on infected cells are the targets for study in this proposal. In this application we propose to understand the genetic and molecular basis for these two forms of immune evasion. Public Health Relevance: The war between hosts and invaders has endured since the rise of the first multicellular organisms. This interaction has been honed to a high level in the relationship between intracellular bacteria and mammals. The main purpose of both the innate and adaptive mammalian immune systems is to avoid the destruction of the host due to bacterial and viral growth. At the same time bacteria and viruses have evolved multiple mechanisms to evade the host immune response. Here we study the mechanism evolved by the intracellular pathogen F. tularensis to modify the host immune response in order to make the bacteria more able to survive and multiply. The study of the interactions of the host with these bacteria will help point out not only the mechanism used by F. tularensis, but also ways in which other pathogens avoid the host immune response. The molecules used will provide important insights into the mechanisms of effective immunity, and provide potential drugable targets for the development of therapeutics, and vaccine adjuvants.