The specific aims of this proposal are: (1) to determine whether two strains of C. neoformans which differ in virulence also differ in their ability to induce TNFalpha production in the lungs and to determine whether TNFalpha expression is T cell dependent (2) to define the role of TNFalpha in mediating the pulmonary clearance of C. neoformans, the recruitment of subpopulations of leukocytes into the lungs, and the development of C. neoformans specific T cells (3) to examine the effect of melanin production by C. neoformans on pulmonary inflammation, cryptococcal clearance and expression of TNFalpha, and (4) to determine whether protective T cell immunity to a virulent strain of C. neoformans can be induced by increasing the levels of TNFalpha in the lungs. The latter experiments may define if adjunct therapy with TNFalpha is feasible in the treatment of this infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29AI038190-05
Application #
2887031
Study Section
AIDS and Related Research Study Section 5 (ARRE)
Program Officer
Dixon (Dmid), Dennis M
Project Start
1995-09-01
Project End
2000-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Traynor, T R; Huffnagle, G B (2001) Role of chemokines in fungal infections. Med Mycol 39:41-50
Huffnagle, G B; Traynor, T R; McDonald, R A et al. (2000) Leukocyte recruitment during pulmonary Cryptococcus neoformans infection. Immunopharmacology 48:231-6
Traynor, T R; Kuziel, W A; Toews, G B et al. (2000) CCR2 expression determines T1 versus T2 polarization during pulmonary Cryptococcus neoformans infection. J Immunol 164:2021-7
Huffnagle, G B; McNeil, L K (1999) Dissemination of C. neoformans to the central nervous system: role of chemokines, Th1 immunity and leukocyte recruitment. J Neurovirol 5:76-81
Huffnagle, G B; McNeil, L K; McDonald, R A et al. (1999) Cutting edge: Role of C-C chemokine receptor 5 in organ-specific and innate immunity to Cryptococcus neoformans. J Immunol 163:4642-6
Huffnagle, G B; Boyd, M B; Street, N E et al. (1998) IL-5 is required for eosinophil recruitment, crystal deposition, and mononuclear cell recruitment during a pulmonary Cryptococcus neoformans infection in genetically susceptible mice (C57BL/6). J Immunol 160:2393-400
Huffnagle, G B; Strieter, R M; McNeil, L K et al. (1997) Macrophage inflammatory protein-1alpha (MIP-1alpha) is required for the efferent phase of pulmonary cell-mediated immunity to a Cryptococcus neoformans infection. J Immunol 159:318-27
Huffnagle, G B; Toews, G B; Burdick, M D et al. (1996) Afferent phase production of TNF-alpha is required for the development of protective T cell immunity to Cryptococcus neoformans. J Immunol 157:4529-36