The outcome of an infection with any given pathogen depends both upon the nature of the pathogen, and the response of the host. Controlling the host-pathogen interaction for the benefit of the host thus requires an understanding both of the pathogen and of the host immune response. Faculty in The Department of Immunology and Infectious Diseases at the Harvard University School of Public Health (HSPH) are uniquely equipped to collaborate to bring these components together. This Department consists of investigators who study the immune response (Glimcher: Project 1, Grusby: Project 2), the interaction of the host and pathogen in vivo (Kramnik: Project 3) and the pathogen itself (Rubin: Project 4). Dr. Glimcher, Project 1, has discovered two gene products that represent early molecular checkpoints in the development of each of these immune response types. T-bet is a transcription factor that dictates the Thl genetic program while the XBP-1 transcription factor controls the generation of plasma cells and hence antibodies. Dr. Grusby, Project 2 has studied the function and modulation of another set of transcription factors, the Stats, which are critical in regulating Type 1 and Type 2 immunity. An additional set of genetic loci that regulate the immune response to Mycobacterium tuberculosis and Francisella tularensis in vivo is the subject of Project 3, Kramnik. This Project also addresses the critical role of the innate rather than the adaptive immune response to the successful control of pathogens. Understanding the structure and function of the pathogen itself is a vital part of any effort to successfully combat pathogens. The genes responsible for virulence of Francisella tularensis will be studied taking advantage of new technologies in genomics and proteomics in Rubin, Project 4. In this proposal, these investigators join with a group specializing in protein structure determination (Petsko: Project 5), and a biotechnology company focused on the immune system with expertise in drug discovery (Allecure: subcontract), to develop a novel strategy for biodefense. In the first component, we recognize that structures of these potential drug targets will provide a framework for virtual screening of combinatorial libraries and for structure-guided drug design. The second component requires productive interaction of academia with industry, the appropriate site for efficient drug discovery. The overall objective of this interdependent, interdisciplinary team is to develop molecules that modulate the host immune system so as to augment the protective effects of vaccines against microbial pathogens.