This is an application for competitive renewal of an ongoing study concerning the nature and mechanism of cell mediated immunity (CMI) to L. pneumophila infection. We wish to further characterize CMI in comparison to other aspects of immunity to L. pneumophila such as humoral immunity in the guinea pig model we have utilized in this laboratory for a number of years as well as a new mouse model which we are developing. We will continue both our in vivo and in vitro studies. In guinea pigs, cell transfer studies will be continued to determined the role of various immune cells and antibodies in resistance and/or recovery from infection by these organisms. The fractionation and identification of cells responsible for transferring resistance to Legionella infection will be examined in some detail. In addition, the mouse model system we have developed will permit the use of both highly resistant and susceptible (strain A/J) mouse strains. Furthermore, resistant mice can be made more susceptible, either by intratracheal infection or treatment with cyclophosphamide. We propose to further identify cells responsible for transfer of resistance and the cell types which respond to the Legionella antigens in vitro by the blast cell transformation assay and by production of soluble mediators of immunity. By use of specific antibody we will purify appropriate cell populations. The role of these cells in resistance to infection will be determined. We will also examine the roles played by IL-1, IL-2 and gamma interferon, as well as TNF, in resistance of experimental animals, especially mice, to Legionella infection. We will continue to examine in detail endocytosis of Legionella in vitro by macrophages, including those obtained from susceptible guinea pigs, mice, and human monocytes and explore the possibility that clathrin mediated endocytosis is involved in Legionella ingestion and intracellular persistence. By these studies we will define various cell classes in the immune response system important in restricting the growth of L. pneumophila, both at the whole animal and at the cellular level. Intact bacterial antigen as well as various purified preparations, including outer membrane protein antigen and lipopolysaccharide, will be used in these experiments. We believe these studies will permit us to determine in detail the nature and mechanisms of cellular immunity and resistance to these important opportunistic intracellular pathogens.
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