CELL BIOLOGY OF THE IMMUNE RESPONSE TO BACTERIA

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Over the past grant period, we have generated considerable data which implicate inflammatory phagocytes as an important component of resistance to infection by facultative intracellular bacteria. Using murine resistance to the facultative intracellular bacterium, Listeria monocytogenes, as a model system, we have shown that T cells which transfer resistance from immune mice to normal mice also transfer the ability to accumulate inflammatory macrophages and neutrophils in response to antigenic challenge. Inflammatory peritoneal neutrophils and macrophages are bactericidal; resident cells are not. Other studies show that the major defect in mice genetically-susceptible to listeria is in their ability to accumulate cells at the site of infection. Finally, macrophages can be selectively stimulated to express tumoricidal but not bactericidal activity, or bactericidal but not tumoricidal activity. Tumoricidal activity by activated macrophages can be dissociated from bactericidal activity. Based on these and other findings, we now wish to test the hypothesis that the major way in which T cells mediate resistance to facultative intracellular bacteria is by causing an influx of inflammatory phagocytes which are inherently bactericidal. It is possible they also enhance the ability of these cells to kill bacteria. To test this hypothesis, we will pursue four specific aims. First, we will clone listeria-reactive T cells and test them for production of biologically-active secretory products which contribute to resistance by enhancing recruitment of inflammatory responses. Second, we will determine whether genetically-susceptible mice have defects at the level of the T cell, the responding inflammatory phagocyte, or both. Third, we will determine whether gamma-interferon can stimulate macrophages to become bactericidal, and whether it can directly or indirectly enhance accumulation of inflammatory bactericidal phagocytes. Finally, we will continue to evaluate biologic properties of listeria components, with an emphasis on identifying and isolating the materials which cause inflammatory responses. It is expected that these studies will contribute to our understanding of how T cells mediate resistance to facultative intracellular bacteria, and perhaps to other microorganisms as well.