The overall goal of the work is to discover how the intracellular growth of the zoopathogenic fungus Histoplasma capsulatum is terminated within macrophages of a recovering host. Such knowledge would be useful in developing immune therapeutic strategies for controlling progressive, disseminated forms of histoplasmosis in which recovery is not the rule. The cells to be used are resident peritoneal macrophages from the C57BL/6 and C3H/HeJ strains of mice and macrophages from the permanent cell lines P338D,and IC-21. Soluble modulators to be studied initially are: Gamma Interferon (IFN-gamma), Lipopoly- saccharide (LPS), Tumor Necrosis Factor (TNF), and Granulocyte/macrophage-Colony Stimulating Factor (GM-CSF).
The specific aims are: (1) to continue studies on the molecular bases for the fungistasis induced in macrophages by recombinant IFN-gamma. The experiments to be conducted will measure the transport, intracellular pool size, and catabolism of methionine, an amino acid whose availability can control intracellular growth of H. capsulatum; and (2) to continue and to augment studies on the ability of IFN-gamma alone and in combination with other immunomodulators to establish an antihistoplasma state with the different sorts of macrophages. The analyses will be conducted by: (i) measuring the intracellular growth and viability of H. capsulatum; (ii) separating by gel electrophoresis the unique peptides formed by IFN-gamma alone or in combination with other modulators; and (iii) assessing the potential role of the peptides in the induced fungistasis or fungicidal state of the macrophages.
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