The bacterial superantigen streptococcal mitogenic exotoxin Z is the major immunoactive agent of Streptococcus pyogenes.
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.
Department of Infectious Diseases, Faculty of Medicine, Imperial College School of Science, Technology, and Medicine, London, United Kingdom.
Meera
M
Unnikrishnan
Daniel M
DM
Altmann
Thomas
T
Proft
Faisal
F
Wahid
Jonathan
J
Cohen
John D
JD
Fraser
Shiranee
S
Sriskandan
D000208:Acute Disease; D000818:Animals; D000942:Antigens, Bacterial / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D001427:Bacterial Toxins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D015139:Blotting, Southern; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D005098:Exotoxins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology; D005838:Genotype; D006683:HLA-DQ Antigens / Q000096:biosynthesis / Q000235:genetics; D015798:HLA-DR1 Antigen / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008934:Mitogens / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010538:Peritonitis / Q000276:immunology / Q000382:microbiology; D016133:Polymerase Chain Reaction / Q000379:methods; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D013290:Streptococcal Infections / Q000276:immunology / Q000382:microbiology; D013297:Streptococcus pyogenes / Q000235:genetics / Q000254:growth & development / Q000276:immunology* / Q000378:metabolism; D018089:Superantigens / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic / Q000276:immunology
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D016207:Cytokines; D005098:Exotoxins; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D015798:HLA-DR1 Antigen; D008934:Mitogens; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018089:Superantigens; C107894:mitogenic exotoxin Z protein, Streptococcus