Defining a novel domain of staphylococcal toxic shock syndrome toxin-1 critical for major histocompatibility complex class II binding, superantigenic activity, and lethality.

Abstract

Staphylococcal toxic shock syndrome toxin-1 (TSST-1) is implicated in the pathogenesis of superantigen-mediated shock. We previously identified TSST-1 residues G31/S32 to be important for major histocompatibility complex (MHC) class II binding, as well as superantigenic and lethal activities. However, the site-directed TSST-1 mutant toxin, G31R, could still induce mitogenesis and low-level TNF alpha secretion, suggesting that additional MHC class II binding sites other than G31/S32 may exist. In the current study, a TSST-1-neutralizing monoclonal antibody, MAb5, was found to inhibit TSST-1 binding to human peripheral blood mononuclear cells, neutralize TSST-1-induced mitogenesis and cytokine secretion, and protect against TSST-1-induced lethality in vivo. Epitope mapping revealed that MAb5 bound to TSST-1 residues 51-56 (T(51-56); 51YYSPAF56). Peptide T(51-56) was synthesized and found to also inhibit TSST-1 binding to human monocytes as well as TSST-1-induced mitogenesis, cytokine secretion, and lethality in vivo. This T(51-56) epitope, located within the beta 3/beta 4 loop, and the previously identified G31/S32 epitope, within the beta 1/beta 2 loop of TSST-1, are separated within the primary sequence, but spatially juxtaposed to each other. Collectively, these findings suggest that a discontinuous epitope comprising of regions within both the beta 1/beta 2 and beta 3/beta 4 loops, are critical for MHC class II binding, and the consequent superantigenic and lethal activities of TSST-1.

• Authors: W W Kum, K B Laupland, A W Chow
• Journal: Canadian journal of microbiology (Can J Microbiol) Vol. 46 Issue 2 Pg. 171-9 (Feb 2000) ISSN: 0008-4166 [Print] Canada
• PMID: 10721486 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Bacterial Toxins
• Cytokines
• Enterotoxins
• Histocompatibility Antigens Class II
• Peptide Fragments
• Superantigens
• enterotoxin F, Staphylococcal

Topics

• Animals
• Antibodies, Monoclonal (biosynthesis, metabolism)
• Bacterial Toxins
• Cells, Cultured
• Cytokines (metabolism)
• Enterotoxins (chemistry, metabolism)
• Epitope Mapping
• Female
• Histocompatibility Antigens Class II (chemistry, metabolism)
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mitosis
• Models, Molecular
• Monocytes (cytology, metabolism)
• Mutagenesis, Site-Directed
• Peptide Fragments (chemistry, pharmacology)
• Protein Binding
• Protein Structure, Tertiary
• Rabbits
• Shock, Septic (chemically induced, mortality)
• Staphylococcus aureus (metabolism)
• Superantigens (chemistry, metabolism)