INFLAMMATION IN RESISTANCE TO BACTERIAL INFECTION

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Infections caused by facultative intracellular pathogens continue to be a significant health problem in the United States and througout the world. Immunotherapeutic strategies for combatting these infections would therefore be of considerable benefit. Murine listeriosis has proven to be a convenient, reproducible, and extremely informative laboratory model for studying immuno-regulation of resistance to infection by facultative intracellular pathogens. Considerable evidence has been provided by our laboratory and others linking anti-listeria resistance with the host's ability to rapidly mobilize an adequate inflammatory response against the invading bacteria. The dual role of T lymphocytes in the regulation of inflammatory responsiveness and antibacterial resistance has been indicated by adpotive transfer studies of listeria-immune T cells which showed that L3T4+ T cells mediate accumulation of inflammatory cells in vivo and Lyt2+ T cells are required for expression of antibacterial resistance. Although these studies have been quite informative, they fail to demonstrate the cellular interactions that occur in vivo when an individual first encounters an invading facultative intracellular pathogen. In the proposed study we will manipulate mouse T cell subsets in vivo by administration of monoclonal anti- L3T4 and anit Lyt2 antibodies and then determine the effect of these treatments on inflammatory responsiveness and antibacterial resistance. Soluble factors produced by these T cells will be assessed for their pro-inflammatory effects in vivo and for their influence on macrophage antibacterial activity in vitro. The possible cytotoxic actio of listeria-immune Lyt2+ T cells against literia-infected macrophages will be investigated as a potential mechanism explaining the protection mediated by these cells in vivo. Besides providing information that will further illuminate our general understanding of T cell-mediated resistance to facultative pathogens, the resuslts of this project will also be germane to the pathogenesis of human listeriosis, which has rapidly emerged as a significant public health problem due to ingestion of listeria-contaminated dairy products.