The goal of this Program Project Grant is to decipher the convergences and differences of the innate immune systems of insects and man. We plan to build on and extend our previous work that has benefited from the collaboration between four laboratories and an administrative core. Project 1 (Ezekowitz Laboratory),"'Pattern Recognition Molecules in Drosophila and Humans", has three Aims. These are to (1) explore the structure and function of a novel pattern recognition receptor, Eater (in collaboration with Projects 2, 3 and 4); (2) utilize a combination of approaches in Drosophila and humans to identify the macrophage receptor for anthrax spores; (3) examine the structure and function of peptidoglycan binding proteins (PGRPs) in flies and humans (in collaboration with Projects 2, 3 and 4). Project 2 (Medzhitov Laboratory), "Phagocytic Pathway in Macrophages and Dendritic Cells", has three Aims: (1) subcellular localization of Toll-like receptors; mechanisms of TLR targeting during phagocytosis; (2) the effect of TLR signaling on phagocytosis in macrophages (in collaboration with Project 1 and 4); (3) the effect of TLRs on phagosome maturation and antigen presentation by dendritic cells. Project 3 (Hoffmann Laboratory) "Recognition and Signaling during Infection in Drosophila" has three Aims: (1) structure-function analysis of PGRPs and GNBPs in Drosophila (in collaboration with Projects 1 and 4); (2) comparative analysis of Drosophila thiolester proteins, TEPs (in collaboration with Project 4); (3) identification of novel immune response genes. Project 4 (Kafatos Laboratory), "Anopheles Immunity and Vector-Pathogen Interactions", has three Aims: (1) comparative analysis of TEPs in the mosquito (in collaboration with Project 3); (2) the role of A. gambiae PGRPs in host defense (in collaboration with Projects 1 and 3); (3) vector innate immune responses to human pathogens. We also propose an Administrative Core that is a vital communications command and control center. The work that we describe has direct relevance to biodefense in the fields of anthrax (Project 1) and vector/pathogen combinations (Project 4). Work in Projects 2 and 3 will provide general insights into innate immunity. We believe that the knowledge gained by successful attainment of the collective aims in this application will lead to information that will have direct applicability to agents that can be manipulated as bioweapons and to emerging infections.