The program project application """"""""Modulation of biodefense responses to bacterial pathogens"""""""" is proposed from the Division of Immunology, U. Connecticut Health Center. This program is composed of three projects and three cores focused on the immune response to bacteria and their products, all of which are included as category B entities on the NIH Biodefense Program list. The program theme is to define the parameters for initiation of anti-microbial immune responses and also examines bacterial products in promoting immunity, or in the case of enterotoxins, pathology, in mucosal tissues. The central hypothesis is that early events in T cell-antigen presenting cell (APC) interactions determine whether or not long-term immunity is induced in response to vaccination, or whether damage is initiated in response to a bacterial toxin. Each project focuses on a unique aspect of the theme to advance our understanding of the immune response to bacterial antigens. Project 1 (Lefrancois) proposes to investigate the T cell response to live or heat killed Listeria monocytogenes. T cell-APC interactions will be examined as will the role of T cell help and Toll-like receptors in optimizing the response. Experiments testing augmentation of the response by bacterial products or costimulatory agonists will be performed in collaboration with the other two projects. Project 2 (McSorley) is focused on the CD4 T cell response to Salmonella typhimurium flagellin and will test whether flagellin can activate APC in vivo and thus be an effective adjuvant or vaccine. Project 3 (Vella) aims to define how staphylococcal enterotoxin B (SEB) influences APC function via T cell interactions and will develop a model of lung mucosa injury to SEB insult. Components of all three projects are aimed at examining T cell-APC interactions following infection or toxin challenge and the innate immune response is also a common topic. These studies provide a natural bridge towards the goal of augmentation of protective immunity. The projects utilize in vivo models and in-depth cellular immunological techniques and are supported by 3 cores: administrative, flow cytometry and fluorescence microscopy/immunohistochemistry. The projects and cores synergistically interact and mutually reinforce one another to achieve the goals of the program. Coupled with strong institutional support, it is anticipated that significant new insights in immune response regulation to pathogens and their byproducts will be obtained.
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