Superantigens may play an important role in cancer, acquired immune deficiency syndrome (AIDS), and arthritis, and staphylococcal enterotoxins are prototype superantigens. The objective of this proposal is to determine the structural basis for staphylococcal enterotoxin superantigen activation of lymphocytes. In particular, the P.I. proposes to determine the structural basis for staphylococcal enterotoxin interaction with both major histocompatibility complex (MHC) class II molecules on antigen-presenting cells and T-cell receptors (TCR) on responding T lymphocytes. This will entail determination of the following structures: certain staphylococcal enterotoxin superantigens, superantigen sites which interact with receptors, and receptor sites which are bound by these superantigens. These studies should help identify structural motifs which convey the property of superantigenicity, and provide insights into how to modulate such activity. The P.I. proposes to achieve the objective through the specific aims which follow: (1) Identify the binding site(s) on staphylococcal enterotoxin A (SEA) and toxic shock syndrome toxin-1 (TSST-1) for MHC class II molecules and TCR using peptides, recombinant native and mutant molecules, and their antibodies; (2) Determine the structures of SEA and TSST-1 peptides as well as recombinant native and mutant molecules to facilitate identification of structural motifs which convey the property of superantigenicity for possible identification of other superantigens in a variety of systems; (3) Determine the agonist / antagonist properties of SEA and TSST-1 receptor binding peptides and recombinant mutant molecules for enhancement of these properties through peptide engineering; (4) Identify the site(s) on MHC class II molecules and TCR that bind SEA and TSST-1; (5) Determine the modulating effect of enterotoxin superantigens on autoimmune diseases such as experimental allergic encephalomyelitis (EAE); and (6) Determine the structural basis for the interaction of the minor lymphocyte stimulating (Mls) superantigens with MHC class II molecules and TCR and its possible relationship to staphylococcal enterotoxin binding to receptors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI025904-06
Application #
3139577
Study Section
Experimental Immunology Study Section (EI)
Project Start
1988-03-01
Project End
1998-02-28
Budget Start
1993-03-01
Budget End
1994-02-28
Support Year
6
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Florida
Department
Type
Schools of Earth Sciences/Natur
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Perrin, G Q; Johnson, H M; Subramaniam, P S (1999) Mechanism of interleukin-10 inhibition of T-helper cell activation by superantigen at the level of the cell cycle. Blood 93:208-16
Torres, B A; Tanabe, T; Subramaniam, P S et al. (1998) Mechanism of HIV pathogenesis: role of superantigens in disease. Alcohol Clin Exp Res 22:188S-192S
Torres, B A; Johnson, H M (1997) Neuroendocrine peptide hormone regulation of immunity. Chem Immunol 69:155-84
Tanabe, T; Torres, B A; Subramaniam, P S et al. (1997) V beta activation by HIV Nef protein: detection by a simple amplification procedure. Biochem Biophys Res Commun 230:509-13
Soos, J M; Schiffenbauer, J; Torres, B A et al. (1997) Superantigens as virulence factors in autoimmunity and immunodeficiency diseases. Med Hypotheses 48:253-9
Hobeika, A C; Johnson, H M (1996) A neutralizing epitope of the superantigen SEA has agonist activity on T cells. Biochem Biophys Res Commun 223:565-71
Torres, B A; Tanabe, T; Johnson, H M (1996) Characterization of Nef-induced CD4 T cell proliferation. Biochem Biophys Res Commun 225:54-61
Hart, D J; Luo, H; Garry, R F (1996) Biochemical characterization of the reverse transcriptase of a human intracisternal A-type particle (HIAP). AIDS Res Hum Retroviruses 12:1367-72
Johnson, H M; Torres, B A; Soos, J M (1996) Superantigens: structure and relevance to human disease. Proc Soc Exp Biol Med 212:99-109
Torres, B A; Tanabe, T; Johnson, H M (1996) Replication of HIV-1 in human peripheral blood mononuclear cells activated by exogenous Nef. AIDS 10:1042-3

Showing the most recent 10 out of 32 publications