This Program aims to define the range of critical responses by which major types of leukocyte effector cells combat distinct, serious mycoses, facilitating collaborative insights into comparative mechanisms of effector response patterns to disparate target fungi with differing susceptibilities to varying leukocyte products. The major objective of Project # 1 (R.D. Diamond and F.R. Sullivan, co-investigators) is to determine the bases for preliminary results indicating disparate effects of human cytokines on killing of Candida albicans hyphae by neutrophils (PMN), even though three cytokines (interferon-gamma, tumor necrosis factor-alpha and granulocyte- macrophage colony stimulating factor) all enhance the PMN respiratory burst primarily required for killing these organisms. Project # 2 (E.H. Smail) aims to characterize biochemically and functionally a product of C. albicans hyphae which inhibits PMN superoxide release and degranulation but not chemotaxis induced by a wide range of agonists, without altering responses to phorbol myristate acetate. Project # 3 (S.M. Levitz) addresses the unique interactions with macrophages of Cryptococcus neoformans yeasts and the role of its capsular polysaccharide in its interactions with both host serum opsonins and phagocytic cells, particularly effects on killing and on specific cellular signal transduction response patterns to stimulation, which will be determined in single cells and cell populations upon activation via single or multiple defined macrophage membrane receptors. Project # 4 (A.M. Sugar) addresses the process by which macrophages act as major effector mediating defenses controlling blastomycosis, aiming to define receptor activation mechanisms, signal transduction pathways, and ultimate responses which determine divergent fungicidal responses against conidia and yeasts, as well as the mechanisms by which cytokines augment inefficient killing by unstimulated macrophages. Project # 5 (W.E. Hauser) focuses on defining the receptor- mediated signal transduction pathways responsible for triggering and controlling direct inhibition and/or killing of C. neoformans and indirect release of mediators by NK cells to augment neutrophil candidacidal effects. Three Core units are designed to provide coordinated facilities for all projects in analysis of individual cell responses, surface receptor and lipid metabolic changes related to signal transduction, and coordination of leukocyte supplies from normal and immunodeficient donors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
1P01AI028408-01
Application #
3091998
Study Section
Special Emphasis Panel (SRC (79))
Project Start
1990-08-01
Project End
1995-01-31
Budget Start
1990-08-01
Budget End
1991-01-31
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Boston University
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02118
Levitz, S M; Tabuni, A; Nong, S H et al. (1996) Effects of interleukin-10 on human peripheral blood mononuclear cell responses to Cryptococcus neoformans, Candida albicans, and lipopolysaccharide. Infect Immun 64:945-51
Kozel, T R; Tabuni, A; Young, B J et al. (1996) Influence of opsonization conditions on C3 deposition and phagocyte binding of large- and small-capsule Cryptococcus neoformans cells. Infect Immun 64:2336-8
Harrison, T S; Levitz, S M (1996) Role of IL-12 in peripheral blood mononuclear cell responses to fungi in persons with and without HIV infection. J Immunol 156:4492-7
Harrison, T S; Kornfeld, H; Levitz, S M (1995) The effect of infection with human immunodeficiency virus on the anticryptococcal activity of lymphocytes and monocytes. J Infect Dis 172:665-71
Meshulam, T; Levitz, S M; Christin, L et al. (1995) A simplified new assay for assessment of fungal cell damage with the tetrazolium dye, (2,3)-bis-(2-methoxy-4-nitro-5-sulphenyl)-(2H)-tetrazolium-5-carboxanil ide (XTT). J Infect Dis 172:1153-6
Sugar, A M; Picard, M; Wagner, R et al. (1995) Interactions between human bronchoalveolar macrophages and Blastomyces dermatitidis conidia: demonstration of fungicidal and fungistatic effects. J Infect Dis 171:1559-62
Stein, D K; Malawista, S E; Van Blaricom, G et al. (1995) Cytoplasts generate oxidants but require added neutrophil granule constituents for fungicidal activity against Candida albicans hyphae. J Infect Dis 172:511-20
Smail, E H; Briza, P; Panagos, A et al. (1995) Candida albicans cell walls contain the fluorescent cross-linking amino acid dityrosine. Infect Immun 63:4078-83
Levitz, S M; Dupont, M P; Smail, E H (1994) Direct activity of human T lymphocytes and natural killer cells against Cryptococcus neoformans. Infect Immun 62:194-202
Goldani, L Z; Picard, M; Sugar, A M (1994) Synthesis of heat-shock proteins in mycelia and yeast forms of Paracoccidioides brasiliensis. J Med Microbiol 40:124-8

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