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Chapter 5 : Toxins and Superantigens of Group A Streptococci

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Abstract:

(group A streptococcus) is a remarkable and versatile human bacterial pathogen that is capable of producing an impressive arsenal of both surface-expressed and secreted virulence factors. This pathogen continues to generate significant morbidity by causing a variety of uncomplicated human diseases such as pharyngitis and skin infections, and more serious diseases such as acute rheumatic and scarlet fevers. In addition, group A streptococci cause some of the most devastating bacterial diseases known, such as necrotizing fasciitis/myositis and the streptococcal toxic shock syndrome (STSS). This chapter focuses on the true exotoxins of group A streptococci with regard to their structure, function, and genetics, as well as their roles in the pathogenesis of human disease. The streptococcal superantigens belong to a larger group of structurally conserved exotoxins that are also produced by coagulase-positive staphylococci. Some group C and group G beta-hemolytic streptococci also produce these toxins. The exotoxins discussed in the chapter are streptococcal pyrogenic toxin type B (SpeB, or cysteine protease), streptococcal pyrogenic toxin type F (SpeF, or mitogenic factor), streptococcal cytolytic toxins, streptokinase, and streptococcal inhibitor of complement (Sic). It has been reported that uncharacterized Spes exist, and they have also been detected in certain group B, C, F, and G streptococcal strains that may mimic the role of the group A streptococcal Spes.

Citation: McCormick J, Peterson M, Schlievert P. 2006. Toxins and Superantigens of Group A Streptococci, p 47-58. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch5

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MHC Class II
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Complement System
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Bacterial Diseases
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Toxic Shock Syndrome
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FIGURE 1

() Structure conservation and models of T-cell activation complexes for streptococcal superantigens. (A) Ribbon diagrams of the crystal structures for streptococcal pyrogenic exotoxin serotypes A, C, H, J, streptococcal superantigen (SSA), and streptococcal mitogenic exotoxin-Z(SMEZ) ( ). (B) Ribbon diagrams demonstrating typical antigen-mediated T-cell activation (left) ( ) and modeled T-cell activation complexes for SpeA (middle) and SpeC (right). The co-crystal structures of SpeA and SpeC in complex with their respective TCR β-chains ( ) and of SpeC in complex with the MHC class II through the zinc-dependent high-affinity binding domain have been determined ( ). In light of recent evidence ( ), it is likely that SpeC also activates T cells in a mode similar to the staphylococcal enterotoxin A model ( ) where the superantigen also engages MHC class II through the generic low-affinity binding domain. The binding architecture for the generic low-affinity MHC class II binding to SpeA and SpeC is modeled using the staphylococcal enterotoxin B-MHC class II co-crystal structure ( ). Note the presence of the zinc ion (magenta) coordinated in the high-affinity binding site for SpeC and that SpeA lacks this zinc site. The TCR α-chain (shown in gray) for both the SpeA and SpeC diagrams is modeled for clarity by superimposition of The α/β TCR shown on the left to the respective TCR β-chains for both superantigens. The figure was generated using Pymol ( ).

Citation: McCormick J, Peterson M, Schlievert P. 2006. Toxins and Superantigens of Group A Streptococci, p 47-58. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch5
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Image of FIGURE 2
FIGURE 2

The presence of the high-affinity, zinc-dependent MHC class II binding domain is associated with approximately 100-fold higher potency of streptococcal superantigens. (A) Sodium dodecyl sulfate polyacrylamide gel demonstrating purity of eight recombinant serotypes of streptococcal superantigens expressed and purified from . Techniques for cloning, expression, and purification have been described ( ). (B) Standard human T-cell proliferation assay using H-thymidine of the eight recombinant streptococcal superantigens. SpeC, SpeG, SpeH, SpeI, SpeJ, and SMEZeach contain the predicted zinc-binding motif found in the β-grasp domain. SpeA and SSA lack this motif and are no longer active at ∼100-fold concentrations higher than the zinc-binding motif containing superantigens. cpm, counts per minute.

Citation: McCormick J, Peterson M, Schlievert P. 2006. Toxins and Superantigens of Group A Streptococci, p 47-58. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch5
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