Cardiac complications, including cardiomyopathy and endocarditis, frequently complicate HIV infections, particularly late in the course of the disease. The etiology of HIV-related cardiotoxicity is unclear, although some believe it is related to concurrent infection with other bacterial and viral pathogens. The grantee has identified toxic shock syndrome toxin-1 (TSST-1) as the major cause of streptococcal toxic shock syndrome (TSS). In addition, he has identified subsets of streptococcal TSS in AIDS patients. The grantee is studying the cardiotoxicity of streptococcal pyrogenic enterotoxins (SPEs, scarlet fever toxins) and staphylocccal on the heart. The long-term goals of this project are two-fold: (1) to evaluate the role of pyrogenic toxin superantigens (PTSAgs), notably SPEs, in causing both acute toxic shock syndrome and vascular illnesses and chronic autoimmune and allergic diseases, and (2) to analyze the structure-function relationships among the SPEs and between the SPEs and staphylococcal enterotoxins and toxic shock syndrome toxin-1, with the intent to clarify the molecular mechanism(s) of action and develop toxoid vaccines against the toxins.
RO1 HL36611 - Patrick Schlievert - University of Minnesota, Minneapolis, MN
This grant is being supported from 1986 to 2001.
Both Group A streptococci and Staphylococcus aureus make superantigens which stimulate tremendous T lymphocyte (predominantly CD4+) proliferation. The structural study of SPE A by the grantee has shown that SPE A structure resembles that of staphylococcal enterotoxins. SPE A and staphylococcal enterotoxins B and C (SEB and SEC) have the ability to bind directly to a T cell receptor ß chain. A model of the T cell receptor-PTSAg-MHC ternary complex reveals that SEC/SEB acts as a partial wedge between the T cell receptor and class II MHC to displace the antigenic peptide away from the T cell receptor combining site. In this way, these toxins are able to circumvent the normal mechanism of T cell activation by specific peptide:class II MHC complexes. The grantee also verified that recombinant exfoliative toxins (ETA) derived from staphylococcus was mitogenic for human T lymphocyte and caused expansion of T cells, thus verifying that the toxin is a superantigen. The X-ray crystal structure indicated that ETA did not have the typical PTSAg structure, but rather, belonged to the chymotrypsin-like family of serine proteases. The grantee has generated many mutant proteins of SEP A. Two mutants which did not exhibit biological toxicity may be useful for vaccination purposes.