Facultative intracellular pathogens continue to pose an important threat to human health, particularly in those whose resistance is impaired by some underlying immunodeficiency. Formerly it was thought that protective immunity against this group of pathogens depended chiefly on T helper cell activation of macrophage bactericidal activity. More recently, it has become evident that there are additional cellular and molecular interactions that substantially influence the pathogenesis of these infections. Murine listeriosis has provided a valuable model for investigating host defense mechanisms to facultative intracellular pathogens. Previous work from our laboratory has demonstrated that several soluble mediators (cytokines) are capable of substantially augmenting host defense. In addition, studies in this and other laboratories have differentiated the contributions of T cell subpopulations to host defense. There are two overall objectives of the research proposed in this application. The first is to understand the integration of cytokines and T cell subsets in cellular immunity against bacterial infection. This will be addressed by in vivo experiments that will use immunocytochemistry to identify T cell subpopulations infiltrating foci of infection, and immunocytochemistry and in situ hybridization to elucidate the profile of cytokines produced by these cells at various times during the course of the infection. This information will be correlated with bacteriological and pathological evaluations of the progression of the protective host response. The second overall objective will be to study in detail the cytolytic activity of spleen cells, obtained from listeria-immunized mice, for listeria-infected macrophages in vitro. The nature of the cytolytic cells, and the mediators required for the afferent and efferent aims of the cytolytic response will be determined. Experiments will also be performed to evaluate the contributions of cytolytic cells to host defense in vivo. Besides being of value as a general model for the immunoregulation of resistance to facultative intracellular pathogens, the information obtained will also increase our understanding of the pathogenesis of listeriosis, which has emerged as a significant public health threat.
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