Histoplasma capsulatum is a dimorphic, pathogenic fungus that produces a wide spectrum of illness ranging from a mild, acute pulmonary infection to a life- threatening progressive, disseminated disease. Successful resolution of infection requires an interaction between T cells and macrophages. Although the latter are the principal habitat and primary effector cells, T cells play a vital and essential role in host resistance to this fungus. We have demonstrated that, in mice, in vivo depletion of either CD4+ or CD8+ T cells is associated with increased severity of infection. Elimination of CD4+ T cells results in death of mice challenged with a sublethal inoculum. Depletion of CD8+ T cells impairs the efficiency of clearance of H. capsulatum from viscera. Thus, optimal clearance of infection requires both T cell subsets. Prior studies with intracellular non-viral pathogens suggest that cytotoxic CD4+ or CD8+ play an important role in recovery from infection. In this proposal, we will test the hypothesis that cytotoxic CD4+ and CD8+ T cells contribute to host defenses against this fungus. The specific objectives of this grant are to: l) Examine the in vitro immunobiological activity of murine H. capsulatum-reactive cytotoxic CD4+ and CD8+ T cells. Specifically, T cell clones will be generated and tested for their capacity to lyse yeast- infected macrophages. Moreover, we will determine the fate of H. capsulatum yeasts in macrophages exposed to cytotoxic T cells, and map the antigens recognized by cytotoxic T cells; 2) Analyze the in vivo functional activity of murine cytotoxic T cell clones. T cell clones will be tested for their capacity to confer protection against a challenge with H. capsulatum, and 3) Determine if human H. capsulatum-reactive CD4+ and CD8+ T cells express cytotoxic activity. Human T cell clones will be analyzed for their ability to lyse yeast-infected human macrophages. Subsequently, we will determine if human cytotoxic T cells alter the fate of yeast cells in human macrophages. These studies will provide further insight into the mechanisms of T cell-mediated immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI023017-10
Application #
2062063
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1985-12-01
Project End
1997-06-30
Budget Start
1995-07-01
Budget End
1996-06-30
Support Year
10
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Allendoerfer, R; Biovin, G P; Deepe Jr, G S (1997) Modulation of immune responses in murine pulmonary histoplasmosis. J Infect Dis 175:905-14
Allendoerfer, R; Deepe Jr, G S (1997) Intrapulmonary response to Histoplasma capsulatum in gamma interferon knockout mice. Infect Immun 65:2564-9
Deepe Jr, G S (1994) Role of CD8+ T cells in host resistance to systemic infection with Histoplasma capsulatum in mice. J Immunol 152:3491-500
Deepe Jr, G S (1994) The immune response to Histoplasma capsulatum: unearthing its secrets. J Lab Clin Med 123:201-5
Newman, S L; Gootee, L; Brunner, G et al. (1994) Chloroquine induces human macrophage killing of Histoplasma capsulatum by limiting the availability of intracellular iron and is therapeutic in a murine model of histoplasmosis. J Clin Invest 93:1422-9
Allendoerfer, R; Magee, D M; Deepe Jr, G S et al. (1993) Transfer of protective immunity in murine histoplasmosis by a CD4+ T-cell clone. Infect Immun 61:714-8
Deepe, G S (1993) Histoplasma capsulatum and V beta a mice: cellular immune responses and susceptibility patterns. J Med Vet Mycol 31:181-8
Henderson, H M; Deepe Jr, G S (1992) Recognition of Histoplasma capsulatum yeast-cell antigens by human lymphocytes and human T-cell clones. J Leukoc Biol 51:432-6
Gomez, F J; Gomez, A M; Deepe Jr, G S (1992) An 80-kilodalton antigen from Histoplasma capsulatum that has homology to heat shock protein 70 induces cell-mediated immune responses and protection in mice. Infect Immun 60:2565-71
Gomez, F J; Gomez, A M; Deepe Jr, G S (1991) Protective efficacy of a 62-kilodalton antigen, HIS-62, from the cell wall and cell membrane of Histoplasma capsulatum yeast cells. Infect Immun 59:4459-64

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