The Bacterial Superantigen Streptococcal Mitogenic Exotoxin Z Is the Major Immunoactive Agent of Streptococcus pyogenes

• Published in: The Journal of immunology (1950) 2002-09, Vol.169 (5), p.2561-2569
• Main Authors: Unnikrishnan, Meera, Altmann, Daniel M, Proft, Thomas, Wahid, Faisal, Cohen, Jonathan, Fraser, John D, Sriskandan, Shiranee
• Format: Article
• Language: English
• Subjects: Acute Disease; Animals; Antigens, Bacterial - biosynthesis; Antigens, Bacterial - genetics; Antigens, Bacterial - immunology; Bacterial Toxins - biosynthesis; Bacterial Toxins - genetics; Bacterial Toxins - immunology; Blotting, Southern; Cell Division - immunology; Cell Line; Cells, Cultured; Cytokines - biosynthesis; Cytokines - metabolism; Exotoxins - biosynthesis; Exotoxins - genetics; Exotoxins - immunology; Exotoxins - metabolism; Gene Expression Regulation - immunology; Genotype; HLA-DQ Antigens - biosynthesis; HLA-DQ Antigens - genetics; HLA-DR1 Antigen - biosynthesis; HLA-DR1 Antigen - genetics; Humans; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Lymphocyte Activation - immunology; Lymphocyte Count; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitogens - biosynthesis; Mitogens - genetics; Mitogens - immunology; Mitogens - metabolism; Peritonitis - immunology; Peritonitis - microbiology; Polymerase Chain Reaction - methods; Receptors, Antigen, T-Cell, alpha-beta - biosynthesis; Spleen - cytology; Spleen - immunology; Spleen - microbiology; Streptococcal Infections - immunology; Streptococcal Infections - microbiology; Streptococcus pyogenes - genetics; Streptococcus pyogenes - growth & development; Streptococcus pyogenes - immunology; Streptococcus pyogenes - metabolism; Superantigens - genetics; Superantigens - immunology; T-Lymphocyte Subsets - cytology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocyte Subsets - pathology; Transcription, Genetic - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.169.5.2561

The gene encoding streptococcal mitogenic exotoxin Z (SMEZ) was disrupted in Streptococcus pyogenes. Despite the presence of other superantigen genes, mitogenic responses in human and murine HLA-DQ transgenic cells were abrogated when cells were stimulated with supernatant from the smez(-) mutant compared with the parent strain. Remarkably, disruption of smez led to a complete inability to elicit cytokine production (TNF-alpha, lymphotoxin-alpha, IFN-gamma, IL-1 and -8) from human cells, when cocultured with streptococcal supernatants. The potent effects of SMEZ were apparent even though transcription and expression of SMEZ were barely detectable. Human Vbeta8(+) T cell proliferation in response to S. pyogenes was SMEZ-dependent. Cells from HLA-DQ8 transgenic mice were 3 logs more sensitive to SMEZ-13 than cells from HLA-DR1 transgenic or wild-type mice. In the mouse, SMEZ targeted the human Vbeta8(+) TCR homologue, murine Vbeta11, at the expense of other TCR T cell subsets. Expression of SMEZ did not affect bacterial clearance or survival from peritoneal streptococcal infection in HLA-DQ8 mice, though effects of SMEZ on pharyngeal infection are unknown. Infection did lead to a rise in Vbeta11(+) T cells in the spleen which was partly reversed by disruption of the smez gene. Most strikingly, a clear rise in murine Vbeta4(+) cells was seen in mice infected with the smez(-) mutant S. pyogenes strain, indicating a potential role for SMEZ as a repressor of cognate anti-streptococcal responses.