Longterm objectives are to study the perturbations of immunoregulation that are associated with infection by the pathogenic yeast, Histoplasma capsulatum (Hc). Studies of experimental pulmonary infection in mice will focus on the flux of lymphocyte subpopulations within infected lungs at serial intervals after intranasal inoculation by means of flow microfluorometry and immunohistological techniques. Antigen- specific vs non-specific recruitment of lymphocytes to infected lungs will be studied. These findings will be correlated with other experiments to assay production of Interleukin I and Interleukin II by cells from infected lung during the course of infection. The role played by T-L3T4+ helper/inducer cells in host defense against Hc infection and in modulation of the granulomatous inflammatory response will be examined by administration of the anti L3T4 monoclonal antibody GK 1.5. Studies on the interactions between unopsonized Hc yeasts and human monocyte-derived macrophages will be carried out to define further the importance of a glycorprotein surface receptor on M0 as the major site for binding of Hc to macrophages. More particularly, the role of the common B chain of the family of adherence glycoproteins CR3/LFA-1/P150-,95 will be determined. Factors governing phagocytosis and killing of Hc yeasts will be analyzed with emphasis on the regulatory effects of Interferon y, fibronectin, and phorbal myristate acetate. Ultrastructural studies will be performed by electron microscopy to examine for the first time, the fate of Hc within human macrophages. Mechanisms by which the organism appears to evade killing will be explored with emphasis on intra-phagosomic events. In humans, possible quantitative abnormalities of immunoregulatory cell populations of peripheral blood will be examined by flow microfluorometry. Functional properties of regulatory cell subsets in peripheral blood will be studied by in vitro techniques with respect to production of the cytokines IL-1 and IL-2 and INFy in response to specific and nonspecific stimuli. Similar studies will be performed on cells by bronchoalveolar lavage of patients with pulmonary histoplasmosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI017339-08
Application #
3127165
Study Section
Bacteriology and Mycology Subcommittee 1 (BM)
Project Start
1980-09-01
Project End
1990-11-30
Budget Start
1987-12-01
Budget End
1988-11-30
Support Year
8
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Newman, S L; Gootee, L; Bucher, C et al. (1991) Inhibition of intracellular growth of Histoplasma capsulatum yeast cells by cytokine-activated human monocytes and macrophages. Infect Immun 59:737-41
Deepe, G S; Bullock, W E (1990) Immunological aspects of fungal pathogenesis. Eur J Clin Microbiol Infect Dis 9:567-79
Schnur, R A; Newman, S L (1990) The respiratory burst response to Histoplasma capsulatum by human neutrophils. Evidence for intracellular trapping of superoxide anion. J Immunol 144:4765-72
Newman, S L; Bucher, C; Rhodes, J et al. (1990) Phagocytosis of Histoplasma capsulatum yeasts and microconidia by human cultured macrophages and alveolar macrophages. Cellular cytoskeleton requirement for attachment and ingestion. J Clin Invest 85:223-30
Gomez, A M; Bullock, W E; Taylor, C L et al. (1988) Role of L3T4+ T cells in host defense against Histoplasma capsulatum. Infect Immun 56:1685-91
Bullock, W E; Wright, S D (1987) Role of the adherence-promoting receptors, CR3, LFA-1, and p150,95, in binding of Histoplasma capsulatum by human macrophages. J Exp Med 165:195-210
Baughman, R P; Kim, C K; Vinegar, A et al. (1986) The pathogenesis of experimental pulmonary histoplasmosis. Correlative studies of histopathology, bronchoalveolar lavage, and respiratory function. Am Rev Respir Dis 134:771-6
Deepe Jr, G S; Taylor, C L; Harris, J E et al. (1986) Modulation of cellular immune responses in mice with disseminated histoplasmosis by recombinant interleukin-2. Infect Immun 53:6-12
Deepe Jr, G S; Smith, J G; Sonnenfeld, G et al. (1986) Development and characterization of Histoplasma capsulatum-reactive murine T-cell lines and clones. Infect Immun 54:714-22
Baughman, R P; Kim, C K; Bullock, W E (1986) Comparative diagnostic efficacy of bronchoalveolar lavage, transbronchial biopsy, and open-lung biopsy in experimental pulmonary histoplasmosis. J Infect Dis 153:376-7

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