Superantigens (SAgs) for B lymphocytes interact via conserved V region framework sites in the B cell antigen receptor (BCR) to target large sets of lymphocytes. We have previously elucidated central structural and immunobiologic properties of protein A of Staphylococcus aureus (SpA), and established SpA as the prototypic experimental B-cell superantigen. Based on an understanding of the molecular basis by which naturally pentameric SpA binds B-cells, we have recently developed the murine T15i Ig """"""""knockin"""""""" system for investigations of the in vivo outcome of SpA exposure. In these mice, most B cells express a VH transgene product that is targeted by SpA, and we have shown that SpA treatments rapidly induce activation-associated apoptotic death of targeted B cells. In the current research program, we will use different forms of SpA to elucidate key mechanisms responsible for BCR-mediated determinations of lymphocyte clonal fate.
The Specific Aims will include:
AIM 1 : To define the nature of the SAg-induced BCR complex responsible for B lymphocyte activation and apoptosis.
AIM 2 : To determine how membrane co-receptors may affect clonal fate after interactions with SpA.
AIM 3 : To investigate how Bcl-2 family members may be involved in determining B-cell clonalfate after interactions with SpA.
AIM 4 : To evaluate how co-exposure to other immunologically active components of S. aureus can affect the outcome of in vivo SpA exposure. These investigations will provide important insights into the fundamental properties of B-cells. In addition, these studies will lead to a better understanding of the immunobiologic activities of a virulence factor from one of the most important causes of life-threatening infection in the US.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI040305-07
Application #
6852691
Study Section
Immunobiology Study Section (IMB)
Program Officer
Miller, Lara R
Project Start
1998-05-01
Project End
2009-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
7
Fiscal Year
2005
Total Cost
$342,000
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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