Chapter 38 : Exotoxins

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

Exotoxins, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555816513/9781555813437_Chap38-1.gif /docserver/preview/fulltext/10.1128/9781555816513/9781555813437_Chap38-2.gif


This chapter talks about exotoxins fall into three general groups: (i) membrane-active agents, (ii) pyrogenic toxin superantigens (PTSAgs), and (iii) exfoliative toxins (ETs). Researchers proposed the existence of delta-toxin as the fourth cytolytic toxin in 1947. Panton-Valentine leukocidin (PVL) and gamma-toxin are two prototypic bicomponent toxins. Unfortunately, the rapid rate of new toxin discovery has resulted in more than one SE being given the same designation in the literature. Therefore, it is now recommended that nomenclature for new PTSAgs be assigned by the International Nomenclature Committee for Staphylococcal Superantigens prior to publication. The major cytokines induced initially include IL-1, tumor necrosis factors alpha and beta, interferon-γ, and IL-2. The ETs have been conclusively implicated in staphylococcal scalded-skin syndrome (SSSS). Two antigenically distinct forms, designated ETA and ETB, are the best characterized ETs and are produced most frequently by phage group II by isolates; strains expressing ETs constitute group IV staphylococcal isolates. Lesions in SSSS and mice are characterized by separation of stratum granulosa cells causing intraepidermal skin peeling.

Citation: Bohach G. 2006. Exotoxins, p 464-477. 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.ch38
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of FIGURE 1

Membrane pore formation by alpha-toxin. (A) Rabbit erythrocyte membrane fragment negatively stained following lysis with alpha-toxin. Arrows designate representative ring-shaped structures (10 nm) on the membrane. (B) Ringshaped alpha-toxin multimers isolated in detergent solution. (Inset) The rings are magnified so that the internal channel (2.5 nm) and ring perimeter (10 nm) are clearly visible.

Citation: Bohach G. 2006. Exotoxins, p 464-477. 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.ch38
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 2

Model for alpha-toxin assembly based on crystallographic data and structure-function experiments. The model depicts the formation of a heptameric ring (α7 and α7*). A cross-section of the ring revealing only four monomers is shown so that the proposed structural alterations are visible. In this model, alpha-toxin is expressed and secreted as a monomer (α1). α1, bound to the target membrane (designated α1*), promotes assembly of the heptamer (α7). In the final stage of assembly, β-sheets in each monomer (depicted as small circles) insert into the membrane, forming a channel, and the N-terminal latches contact adjacent monomers, rendering them resistant to proteolysis.

Citation: Bohach G. 2006. Exotoxins, p 464-477. 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.ch38
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 3

Properties of staphylococcal beta-toxin. (A) Sphingomyelin chemical formula showing beta-toxin cleavage site resulting in generation of phosphorylcholine and ceramide. (B) Scanning electron micrograph showing lesions in human erythrocyte membranes caused by beta-toxin after shifting the temperature to 4°C.

Citation: Bohach G. 2006. Exotoxins, p 464-477. 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.ch38
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 4

Molecular aspects of staphylococcal bicomponent toxins. Organization of bicomponent toxin genes in a strain harboring both the and loci. Any S and F component may combine to generate a unique bicomponent toxin. The two prototype bicomponent toxins, PVL and deltatoxin, are composed of LukS-PV+LukF-PV and HlgA+HlgB, respectively.

Citation: Bohach G. 2006. Exotoxins, p 464-477. 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.ch38
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 5

Structural properties and receptor interactions of PTSAgs. (A) A structural comparison of SEC3 and TSST-1. Ribbon diagrams shown are based on crystal structures published for the two toxins ( ). The two structures are oriented so that the TCR-binding cavity in each is located at the top and the cysteine loop, unique to the SEs, is on the upper right-hand corner of SEC3. Both toxins possess a similar domain organization and an overall topology despite having several important differences as discussed in the text. (B) A model of the trimolecular complex with SEB or SEC bound to TCR and MHC-II (adapted from results of references and ). In this model, SAgs orient the two receptors away from each other, inducing an aberrant mechanism of T-cell activation. Note that antigenic peptide associated with MHC-II is positioned away from the TCR-binding site.

Citation: Bohach G. 2006. Exotoxins, p 464-477. 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.ch38
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 6

Ribbon diagram of the ETA crystal structure showing important functional features. Similar to other chymotrypsinlike proteases, ETA has two β-barrel domains and a C-terminal α-helix. The N-terminal domain, which includes a highly charged α-helix, is unique and is suspected to be involved in receptor binding. The positions of residues H72, D102, and S195, comprising the putative catalytic triad, are superimposable with the analogous residues of α-thrombin. D164 in loop D controls access of substrate to the protease active site by hydrogen bonding to G193. This causes the P192-G193 peptide bond to flip 180 degrees compared to that seen in other serine proteases and may explain the lack of demonstrable proteolytic activity in vitro. Binding of the N-terminal α-helix to its receptor has been proposed to cause a shift in the position of loop D and thereby the P192-G193 peptide bond, allowing access to the active site in vivo ( ).

Citation: Bohach G. 2006. Exotoxins, p 464-477. 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.ch38
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Aarestrup, F. M.,, H. D. Larsen,, N. H. Eriksen,, C. S. Elsberg,, and N. E. Jensen. 1999. Frequency of alpha- and beta-haemolysin in Staphylococcus aureus of bovine and human origin. A comparison between pheno- and geno-type and variation in phenotypic expression. APMIS 107: 425 430.
2. Ahrens, P.,, and L. O. Andresen. 2004. Cloning and sequence analysis of genes encoding Staphylococcus hyicus exfoliative toxin types A, B, C, and D. J. Bacteriol. 186: 1833 1837.
3. Alber, G.,, D. K. Hammer,, and B. Fleischer. 1990. Relationship between enterotoxic- and T lymphocyte-stimulating activity of staphylococcal enterotoxin B. J. Immunol. 144: 4501 4506.
4. Alber, G.,, P. H. Scheuber,, B. Reck,, B. Sailer-Kramer,, A. Hartmann,, and D. K. Hammer. 1989. Role of substance P in immediate-type skin reactions induced by staphylococcal enterotoxin B in unsensitized monkeys. J. Allergy Clin. Immunol. 84: 880 885.
5. Al-Daccak, R.,, K. Mehindate,, F. Damdoumi,, P. Etongue-Mayer,, H. Nilsson,, P. Antonsson,, M. Sundstrom,, M. Dohlsten,, R. P. Sekaly,, and W. Mourad. 1998. Staphylococcal enterotoxin D is a promiscuous superantigen offering multiple modes of interactions with the MHC class II receptors. J. Immunol. 160: 225 232.
6. Alouf, J. E., 1977. Cell membranes and cytolytic bacterial toxins, p. 220 270. In P. Cuatrecasas (ed.), Receptors and Recognition, series B, vol. 1. The Specificity and Action of Animal, Bacterial and Plant Toxins. Chapman and Hall Ltd., London, United Kingdom
7. Amagai, M.,, N. Matsuyoshi,, Z. H. Wang,, C. Andl,, and J. R. Stanley. 2000. Toxin in bullous impetigo and staphylococcal scalded-skin syndrome targets desmoglein 1. Nat. Med. 6: 1275 1277.
8. Amagai, M.,, T. Yamaguchi,, Y. Hanakawa,, K. Nishifuji,, M. Sugai,, and J. R. Stanley. 2002. Staphylococcal exfoliative toxin B specifically cleaves desmoglein 1. J. Invest. Dermatol. 118: 845 850.
9. Arbuthnott, J. P., 1982. Bacterial cytolysins (membranedamaging toxins), p. 107 129. In P. Cohen, and S. van Heyningen (ed.), Molecular Action of Toxins and Viruses. Elsevier Biomedical Press, Amsterdam, The Netherlands.
10. Bailey, C. J.,, B. P. Lockhart,, M. B. Redpath,, and T. P. Smith. 1995. The epidermolytic (exfoliative) toxins of Staphylococcus aureus. Med. Microbiol. Immunol. 184: 53 61.
11. Bailey, C. J.,, and M. B. Redpath. 1992. The esterolytic activity of epidermolytic toxins. Biochem. J. 284: 177 180.
12. Bayles, K. W.,, and J. J. Iandolo. 1989. Genetic and molecular analyses of the gene encoding staphylococcal enterotoxin D. J. Bacteriol. 171: 4799 4806.
13. Bhakdi, S.,, and J. Tranum-Jensen. 1991. Alpha-toxin of Staphylococcus aureus. Microbiol. Rev. 55: 733 751.
14. Bohach, G. A.,, D. J. Fast,, R. D. Nelson,, and P. M. Schlievert. 1990. Staphylococcal and streptococcal pyrogenic toxins involved in toxic shock syndrome and related illnesses. Crit. Rev. Microbiol. 17: 251 272.
15. Bohach, G. A.,, L. M. Jablonski,, C. F. Deobald,, Y. I. Chi,, and C. V. Stauffacher,. 1995. Functional domains of staphylococcal enterotoxins, p. 339 356. In M. Ecklund,, J. L. Richard,, and K. Mise (ed.), Molecular Approaches to Food Safety: Issues Involving Toxic Microorganisms. Alaken, Inc., Fort Collins, Colo.
16. Boyle, T.,, V. Lancaster,, R. Hunt,, P. Gemski,, and M. Jett. 1994. Method for simultaneous isolation and quantitation of platelet activating factor and multiple arachidonate metabolites from small samples: analysis of effects of Staphylococcus aureus enterotoxin B in mice. Anal. Biochem. 216: 373 382.
17. Buerke, M.,, U. Sibelius,, U. Grandel,, U. Buerke,, F. Grimminger,, W. Seeger,, J. Meyer,, and H. Darius. 2002. Staphylococcus aureus alpha toxin mediates polymorphonuclear leukocyte-induced vasocontraction and endothelial dysfunction. Shock 17: 30 35.
18. Caiazza, N. C.,, and G. A. O’Toole. 2003. Alpha-toxin is required for biofilm formation by Staphylococcus aureus. J. Bacteriol. 185: 3214 3217.
19. Cavarelli, J.,, G. Prevost,, W. Bourguet,, L. Moulinier,, B. Chevrier,, B. Delagoutte,, A. Bilwes,, L. Mourey,, S. Rifai,, Y. Piemont,, and D. Moras. 1997. The structure of Staphylococcus aureus epidermolytic toxin A, an atypic serine protease, at 1.7 Å resolution. Structure 5: 813 824.
20. Chintagumpala, M. M.,, J. A. Mollick,, and R. R. Rich. 1991. Staphylococcal toxins bind to different sites on HLA-DR. J. Immunol. 147: 3876 3881.
21. Choi, Y.,, B. Kotzin,, L. Herron,, J. Callahan,, P. Marrack,, and J. Kappler. 1989. Interaction of Staphylococcus aureus toxin superantigens with human T cells. Proc. Natl. Acad. Sci. USA 86: 8941 8945.
22. Coleman, D. C.,, J. P. Arbuthnott,, H. M. Pomeroy,, and T. H. Birkbeck. 1986. Cloning and expression in Escherichia coli and Staphylococcus aureus of the beta-lysin determinant from Staphylococcus aureus: evidence that bacteriophage conversion of beta-lysin activity is caused by insertional inactivation of the beta-lysin determinant. Microb. Pathog. 1: 549 564.
23. Colin, D. A.,, I. Mazurier,, S. Sire,, and V. Finck-Barbancon. 1994. Interaction of the two components of leukocidin from Staphylococcus aureus with human polymorphonuclear leukocyte membranes: sequential binding and subsequent activation. Infect. Immun. 62: 3184 3188.
24. Colin, D. A.,, O. Meunier,, L. Staali,, H. Monteil,, and G. Prevost. 1996. Action mode of two components poreforming leucotoxins from Staphylococcus aureus. Med. Microbiol. Immunol. 185: 107 114.
25. Cooney, J.,, Z. Kienle,, T. J. Foster,, and P. W. O’Toole. 1993. The gamma-hemolysin locus of Staphylococcus aureus comprises three linked genes, two of which are identical to the genes for the F and S components of leukocidin. Infect. Immun. 61: 678 771.
26. Deringer, J. R.,, R. J. Ely,, S. R. Monday,, C. V. Stauffacher,, and G. A. Bohach. 1997 Vβ-dependent stimulation of bovine and human T cells by host-specific staphylococcal enterotoxins. Infect. Immun. 65: 4048 4054.
27. Deringer, J. R.,, R. J. Ely,, C. V. Stauffacher,, and G. A. Bohach. 1996. Subtype-specific interactions of type C staphylococcal enterotoxins with the T-cell receptor. Mol. Microbiol. 22: 523 534.
28. Dhople, V. M.,, and R. Nagaraj. 2005. Conformation and activity of delta-lysin and its analogs. Peptides 26: 217 225.
29. Dufourc, E. J.,, J. Dufourcq,, T. H. Birkbeck,, and J. H. Freer. 1990. δ-Haemolysin from Staphylococcus aureus and model membranes. A solid-state 2H-NMR and 31P-NMR study. Eur. J. Biochem. 187: 581 587.
30. Dziewanowska, K.,, V. E. Edwards,, J. R. Deringer,, G. A. Bohach,, and D. J. Guerra. 1996. Comparison of the β-toxins from Staphylococcus aureus and Staphylococcus intermedius. Arch. Biochem. Biophys. 335: 102 108.
31. Earhart, C. A.,, D. T. Mitchell,, D. L. Murray,, D. M. Pinheiro,, M. Matsumura,, P. M. Schlievert,, and D. H. Ohlendorf. Structures of five mutants of toxic shock syndrome toxin-1 with reduced biological activity. Biochemistry 37: 7194 7202.
32. Edwards, V. M.,, J. R. Deringer,, S. D. Callantine,, C. F. Deobald,, P. H. Berger,, V. Kapur,, C. V. Stauffacher,, and G. A. Bohach. 1997. Characterization of the canine type C enterotoxin produced by Staphylococcus intermedius pyoderma isolates. Infect. Immun. 65: 2346 2352.
33. Elwell, M. R.,, C. T. Liu,, R. O. Spertzel,, and W. R. Beisel. 1975. Mechanisms of oral staphylococcal enterotoxin B-induced emesis in the monkey. Proc. Soc. Exp. Biol. Med. 148: 424 427.
34. Essmann, F.,, H. Bantel,, G. Totzke,, I. H. Engels,, B. Sinha,, K. Schulze-Osthoff,, and R. U. Janicke. 2003. Staphylococcus aureus alpha-toxin-induced cell death: predominant necrosis despite apoptotic caspase activation. Cell Death Differ. 10: 1260 1272.
35. Fields, B. A.,, E. L. Malchiodi,, H. Li,, X. Ysern,, C. V. Stauffacher,, P. M. Schlievert,, K. Karjalainen,, and R. A. Mariuzza. 1996. Crystal structure of a T-cell receptor betachain complexed with a superantigen. Nature 384: 188 192.
36. Finck-Barbancon, V.,, G. Duportail,, O. Meunier,, and D. A. Colin. 1993. Pore formation by two-component leukocidin from Staphylococcus aureus within the membrane of human polymorphonuclear leukocytes. Biochim. Biophys. Acta 1182: 275 282.
37. Fitzgerald, J. R.,, S. D. Reid,, E. Ruotsalainen,, T. J. Tripp,, M. Liu,, R. Cole,, P. Kuusela,, P. M. Schlievert,, A. Jarvinen,, and J. M. Musser. 2003. Genome diversification in Staphylococcus aureus: molecular evolution of a highly variable chromosomal region encoding the Staphylococcal exotoxin-like family of proteins. Infect. Immun. 71: 2827 2838.
38. Fleischer, B.,, and C. J. Bailey. 1992. Recombinant epidermolytic (exfoliative) toxin A of Staphylococcus aureus is not a superantigen. Med. Microbiol. Immunol. 180: 273 279.
39. Florquin, S.,, and L. Aaldering. 1997. Superantigens: a tool to gain new insight into cellular immunity. Res. Immunol. 148: 373 386.
40. Foster, T. J.,, M. O’Reilly,, P. Phonimdaeng,, J. Cooney,, A. H. Patel,, and A. J. Bramley,. 1990. Genetic studies of virulence factors of Staphylococcus aureus. Properties of coagulase and gamma-toxin and the role of alpha-toxin, beta-toxin and protein A in the pathogenesis of S. aureus infections, p. 403 417. In R. P. Novick (ed.), Molecular Biology of the Staphylococci. VCH, Cambridge, New York, N.Y.
41. Fraser, J. D. 1989. High-affinity binding of staphylococcal enterotoxins A and B to HLA-DR. Nature 339: 221 223.
42. Furoda, M.,, T. Ohta,, I. Uchiyama,, T. Baba,, H. Yuzawa,, I. Kobayashi,, L. Cui,, A. Oguchi,, K. Aoki,, Y. Nagai,, J. Lian,, T. Ito,, M. Kanamori,, H. Matsumaru,, A. Maruyama,, H. Murakami,, A. Hosoyama,, Y. Mizutani-Ui,, N. K. Takahashi,, T. Sawano,, R. Inoue,, C. Kaito,, K. Sekimizu,, H. Hirakawa,, S. Kuhara,, S. Goto,, J. Yabuzaki,, M. Kanehisa,, A. Yamashita,, K. Oshima,, K. Furuya,, C. Yoshino,, T. Shiba,, M. Hattori,, N. Ogasawara,, H. Hayashi,, and K. Hiramatsu. 2001. Whole genome sequencing of methicillin-resistant Staphylococcus aureus. Lancet 357: 1225 1240.
43. Gase, K.,, J. J. Ferretti,, C. Primeaux,, and W. M. Mc-Shan. 1999. Identification, cloning, and expression of the CAMP factor gene (cfa) of group A streptococci. Infect. Immun. 67: 4725 4731.
44. Gillet, Y.,, B. Issartel,, P. Vanhems,, J. C. Fournet,, G. Lina,, M. Bes,, F. Vandenesch,, Y. Piemont,, N. Brousse,, D. Floret,, and J. Etienne. 2002. Association between Staphylococcus aureus strains carrying gene for Panton-Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patients. Lancet 359: 753 759.
45. Grundstrom, S.,, L. Cederbom,, A. Sundstedt,, P. Scheipers,, and F. Ivars. 2003. Superantigen-induced regulatory T cells display different suppressive functions in the presence or absence of natural CD4+CD25+ regulatory T cells in vivo. J. Immunol. 170: 5008 5017.
46. Goerke, C.,, S. Matias y Papenberg,, S. Dasbach,, K. Dietz,, R. Ziebach,, B. C. Kahl,, and C. Wolz. 2004. Increased frequency of genomic alterations in Staphylococcus aureus during chronic infection is in part due to phage mobilization. J. Infect. Dis. 189: 724 734.
47. Gravet, A.,, D. Colin,, R. Keller,, H. Giradot,, H. Monteil,, and G. Prevost. 1998. Characterization of a novel structural member, LukE-LukD, of the bi-component staphylococcal leucotoxins family. FEBS Lett. 436: 202 208.
48. Guillet, V.,, P. Roblin,, S. Werner,, M. Coraiola,, G. Menestrina,, H. Monteil,, G. Prevost,, and L. Mourey. 2004. Crystal structure of leucotoxin S component: new insight into the staphylococcal beta-barrel pore-forming toxins. J. Biol. Chem. 279: 41028 41037.
49. Hanakawa, Y.,, N. M. Schechter,, C. Lin,, L. Garza,, H. Li,, T. Yamaguchi,, Y. Fudaba,, K. Nishifuji,, M. Sugai,, M. Amagai,, and J. R. Stanley. 2002. Molecular mechanisms of blister formation in bullous impetigo and staphylococcal scalded skin syndrome. J. Clin. Invest. 110: 53 60.
50. Hanakawa, Y.,, T. Selwood,, D. Woo,, C. Lin,, N. M. Schechtern,, and J. R. Stanley. 2003. Calcium-dependent conformation of desmoglein 1 is required for its cleavage by exfoliative toxin. J. Invest. Dermatol. 121: 383 389.
51. Harris, T. O.,, and M. J. Betley. 1995. Biological activities of staphylococcal enterotoxin type A mutants with N-terminal substitutions. Infect. Immun. 63: 2133 2140.
52. Haslinger, B.,, K. Strangfeld,, G. Peters,, K. Schulze-Osthoff,, and B. Sinha. 2003. Staphylococcus aureus alphatoxin induces apoptosis in peripheral blood mononuclear cells: role of endogenous tumour necrosis factor-alpha and the mitochondrial death pathway. Cell Microbiol. 5: 729 741.
53. Hildebrand, A.,, M. Roth,, and S. Bhakdi. 1991. Staphylococcus aureus alpha-toxin: dual mechanisms of binding to target cells. J. Biol. Chem. 266: 17195 17200.
54. Holmberg, S. D.,, and P. A. Blake. 1984. Staphylococcal food poisoning in the United States. New facts and old misconceptions. JAMA 251: 487 489.
55. Hovde, C. J.,, J. C. Marr,, M. L. Hoffmann,, S. P. Hackett,, Y. I. Chi,, K. K. Crum,, D. L. Stevens,, C. V. Stauffacher,, and G. A. Bohach. 1994. Investigation of the role of the disulphide bond in the activity and structure of staphylococcal enterotoxin C1. Mol. Microbiol. 13: 897 909.
56. Hudson, K. R.,, R. E. Tiedemann,, R. G. Urban,, S. C. Lowe,, J. L. Strominger,, and J. D. Fraser. 1995. Staphylococcal enterotoxin A has two cooperative binding sites on major histocompatibility complex class II. J. Exp. Med. 182: 711 720.
57. Jarraud, S.,, G. J. Lyon,, A. M. Figueiredo,, L. Gerard,, F. Vandenesch,, J. Etienne,, T. W. Muir,, and R. P. Novick. 2000. Exfoliatin-producing strains define a fourth agr specificity group in Staphylococcus aureus. J. Bacteriol. 182: 6517 6522.
58. Jardetsky, T. S.,, J. H. Brown,, J. C. Gorga,, L. J. Stern,, R. G. Urban,, Y. I. Chi,, C. V. Stauffacher,, J. L. Strominger,, and D. C. Wiley. 1994. Three-dimensional structure of a human class II histocompatibility molecule complexed with superantigen. Nature 368: 711 718.
59. Jarraud, S.,, M. A. Peyrat,, A. Lim,, A. Tristan,, M. Bes,, C. Mougel,, J. Etienne,, F. Vandenesch,, M. Bonneville,, and G. Lina. 2001. egc, a highly prevalent operon of enterotoxin gene, forms a putative nursery of superantigens in Staphylococcus aureus. J. Immunol. 166: 669 677.
60. Jarvis, W. D.,, R. N. Kolesnick,, F. A. Fornari,, R. S. Traylor,, D. A. Gewirtz,, and S. Grant. 1994. Induction of apoptotic DNA damage and cell death by activation of the sphingomyelin pathway. Proc. Natl. Acad. Sci. USA 91: 73 77.
61. Jonas, D.,, I. Walev,, T. Berger,, M. Liebetrau,, M. Palmer,, and S. Bhakdi. 1994. Novel path to apoptosis: small transmembrane pores created by staphylococcal alpha-toxin in T lymphocytes evoke internucleosomal DNA degradation. Infect. Immun. 62: 1304 1312.
62. Kaneko, J.,, O. Toshiko,, T. Tomita,, and Y. Kamio. 1997. Sequential binding of staphylococcal γ-hemolysin to human erythrocytes and complex formation of the hemolysin on the cell surface. Biosci. Biotechnol. Biochem. 61: 846 851.
63. Kappler, J.,, B. Kotzin,, L. Herron,, E. W. Gelfand,, R. D. Bigler,, A. Boylston,, S. Carrel,, D. N. Posnett,, Y. Choi,, and P. Marrack. 1989. V beta-specific stimulation of human T cells by staphylococcal toxins. Science 244: 811 813.
64. Kim, C. S.,, S. Y. Jeon,, Y. G. Min,, C. Rhyoo,, J. W. Kim,, J. B. Yun,, S. W. Park,, and T. Y. Kwon. 2000. Effects of beta-toxin of Staphylococcus aureus on ciliary activity of nasal epithelial cells. Laryngoscope 110: 2085 2088.
65. Kim, J.,, R. G. Urban,, J. L. Strominger,, and D. C. Wiley. 1994. Toxic shock syndrome toxin-1 complexed with a class II major histocompatibility molecule HLA-DR1. Science 266: 1870 1874.
66. Leder, L.,, A. Llera,, P. M. Lavoie,, M. I. Lebedeva,, H. Li,, R. P. Sekaly,, G. A. Bohach,, P. J. Gahr,, P. M. Schlievert,, K. Karjalainen,, and R. A. Mariuzza. 1998. A mutational analysis of the binding of staphylococcal enterotoxins B and C3 to the T cell receptor beta chain and major histocompatibility complex class II. J. Exp. Med. 187: 823 833.
67. Letertre, C.,, S. Perelle,, F. Dilasser,, and P. Fach. 2003. Identification of a new putative enterotoxin SEU encoded by the egc cluster of Staphylococcus aureus. J. Appl. Microbiol. 95: 38 43.
68. Lina, G.,, G. A. Bohach,, S. P. Nair,, K. Hiramatsu,, E. Jouvin-Marche,, and R. Mariuzza, International Nomenclature Committee for Staphylococcal Superantigens. 2004. Standard nomenclature for the superantigens expressed by Staphylococcus. J. Infect. Dis. 189: 2334 2336.
69. Lina, G.,, Y. Piemont,, F. Godail-Gamot,, M. Bes,, M. O. Peter,, V. Gauduchon,, F. Vandenesch,, and J. Etienne. 1999. Involvement of Panton-Valentine leukocidin-producing Staphylococcus aureus in primary skin infections and pneumonia. Clin. Infect. Dis. 29: 1128 1132.
70. Low, D. K. R.,, and J. H. Freer. 1977. Biological effects of highly purified β-lysin (sphingomyelinase C) from Staphylococcus aureus. FEMS Microbiol. Lett. 2: 133 138.
71. Mahlknecht, U.,, M. Herter,, M. K. Hoffmann,, D. Niethammer,, and G. E. Dannecker. 1996. The toxic shock syndrome toxin-1 induces anergy in human T cells in vivo. Hum. Immunol. 45: 42 45.
72. Marshall, M. J.,, G. A. Bohach,, and D. F. Boehm. 2000. Characterization of Staphylococcus aureus beta-toxin induced leukotoxicity. J. Nat. Toxins 9: 125 138.
73. Melish, M. E.,, and L. A. Glasgow. 1970. The staphylococcal scalded skin syndrome: development of an experimental model. N. Engl. J. Med. 282: 1114 1119.
74. Mellor, I. R.,, D. H. Thomas,, and M. S. P. Sansom. 1988. Properties of ion channels formed by Staphylococcus aureus δ-toxin. Biochim. Biophys. Acta 942: 280 294.
75. Mempel, M.,, C. Schnopp,, M. Hojka,, H. Fesq,, S. Weidinger,, M. Schaller,, H. C. Korting,, J. Ring,, and D. Abeck. 2002. Invasion of human keratinocytes by Staphylococcus aureus and intracellular bacterial persistence represent haemolysin-independent virulence mechanisms that are followed by features of necrotic and apoptotic keratinocyte cell death. Br. J. Dermatol. 146: 943 951.
76. Menestrina, G.,, M. D. Serra,, and G. Prevost. 2001. Mode of action of beta-barrel pore-forming toxins of the staphylococcal alpha-hemolysin family. Toxicon 39: 1661 1672.
77. Miles, G.,, L. Movileanu,, and H. Bayley. 2002. Subunit composition of a bicomponent toxin: staphylococcal leukocidin forms an octameric transmembrane pore. Protein Sci. 11: 894 902.
78. Monday, S. R.,, and G. A. Bohach,. 1999. Genetic, structural, biological, pathophysiological and clinical aspects of Staphylococcus aureus enterotoxins and toxic shock syndrome toxin-1, p. 589 610. In J. E. Alouf, and J. H. Freer (ed.), Sourcebook of Bacterial Protein Toxins. Academic Press, London, United Kingdom.
79. Monday, S. R.,, and G. A. Bohach. 2000. Genes encoding staphylococcal enterotoxins are linked and separated by DNA related to other staphylococcal enterotoxins. J. Nat. Toxins 10: 1 8.
80. Monday, S. R.,, G. M. Vath,, W. A. Ferens,, C. Deobald,, J. V. Rago,, P. J. Gahr,, D. Monie,, J. J. Iandolo,, S. K. Chapes,, W. C. Davis,, D. H. Ohlendorf,, P. M. Schlievert,, and G. A. Bohach. 1999. Unique superantigen activity of staphylococcal exfoliative toxins. J. Immunol. 181: 4550 4559.
81. Munson, S. H.,, M. T. Tremaine,, M. J. Betley,, and R. A. Welch. 1998. Identification and characterization of staphylococcal enterotoxin types G and I from Staphylococcus aureus. Infect. Immun. 66: 3337 3348.
82. Narita, S.,, J. Kaneko,, J. Chiba,, Y. Piemont,, S. Jarraud,, J. Etienne,, and Y. Kamio. 2001. Phage conversion of Panton-Valentine leukocidin in Staphylococcus aureus: molecular analysis of a PVL-converting phage, ϕSLT. Gene 268: 195 206.
83. Noda, M.,, and I. Kato,. 1991. Leukocidal toxins, p. 243 251. In J. E. Alouf, and J. H. Freer (ed.), Sourcebook of Bacterial Protein Toxins. Academic Press, London, United Kingdom.
84. O’Callaghan, R. J.,, M. C. Callegan,, J. M. Moreau,, L. C. Green,, T. J. Foster,, O. M. Hartford,, L. S. Engel,, and J. M. Hill. 1997. Specific roles of alpha-toxin and beta-toxins during Staphylococcus corneal infection. Infect. Immun. 65: 1571 1578.
85. Omoe, K.,, K. Imanishi,, D. L. Hu,, H. Kato,, H. Takahashi-Omoe,, A. Nakane,, T. Uchiyama,, and K. Shinagawa. 2004. Biological properties of staphylococcal enterotoxin-like toxin type R. Infect. Immun. 72: 3664 3667.
86. Omoe, K.,, D. L. Hu,, H. Takahashi-Omoe,, A. Nakane,, and K. Shinagawa. 2003. Identification and characterization of a new staphylococcal enterotoxin-related putative toxin encoded by two kinds of plasmids. Infect. Immun. 71: 6088 6094.
87. Onogawa, T. 2002. Staphylococcal alpha-toxin synergistically enhances inflammation caused by bacterial components. FEMS Immunol. Med. Microbiol. 33: 15 21.
88. Orwin, P. M.,, J. Fitzgerald,, D. Y. Leung,, J. A. Gutierrez,, G. A. Bohach,, and P. M. Schlievert. 2003. Characterization of Staphylococcus aureus enterotoxin L. Infect. Immun. 71: 2916 2919.
89. Orwin, P. M.,, D. Y. Leung,, D. H. Donahue,, R. P. Novick,, and P. M. Schlievert. 2001. Biochemical and biological properties of Staphylococcal enterotoxin K. Infect. Immun. 69: 360 366.
90. Orwin, P. M.,, D. Y. Leung,, T. J. Tripp,, G. A. Bohach,, C. A. Earhart,, D. H. Ohlendorf,, and P. M. Schlievert. 2002. Characterization of a novel staphylococcal enterotoxin- like superantigen, a member of the group V subfamily of pyrogenic toxins. Biochemistry 41: 14033 14040.
91. Ozawa, T.,, J. Kaneko,, and Y. Kamio. 1995. Essential binding of LukF of staphylococcal γ-hemolysin followed by the binding of HγII for the hemolysis of human erythrocytes. Biosci. Biotech. Biochem. 559: 1181 1183.
92. Ozawa, T.,, J. Kaneko,, H. Narija,, K. Izaki,, and Y. Kamio. 1994. Inactivation of the γ-hemolysin HγII component by addition of monoganglioside G MI to human erythrocyte. Biosci. Biotech. Biochem. 58: 602 605.
93. Park, P. W.,, T. J. Foster,, E. Nishi,, S. J. Duncan,, M. Klagsbrun,, and Y. Chen. 2004. Activation of syndecan-1 ectodomain shedding by Staphylococcus aureus alpha-toxin and beta-toxin. J. Biol. Chem. 279: 251 258.
94. Parsonnet, J., 1998. Case definition of staphylococcal TSS: a proposed revision incorporating laboratory findings, p. 15. In F. Arbuthnott, and B. Furman (ed.), Proceedings of the European Conference on Toxic Shock Syndrome. T he Royal Society of Medicine Limited, London, United Kingdom.
95. Petersson, K.,, H. Pettersson,, N. J. Skartved,, B. Walse,, and G. Forsberg. 2003. Staphylococcal enterotoxin H induces V alpha-specific expansion of T cells. J. Immunol. 170: 4148 4154.
96. Petersson, K.,, M. Hakansson,, H. Nilsson,, G. Forsberg,, L. A. Svensson,, A. Liljas,, and B. Walse. 2001. Crystal structure of a superantigen bound to MHC class II displays zinc and peptide dependence. EMBO J. 20: 3306 3312.
97. Plano, L. R.,, B. Adkins,, M. Woischnik,, R. Ewing,, and C. M. Collins. 2001. Toxin levels in serum correlate with the development of staphylococcal scalded skin syndrome in a murine model. Infect. Immun. 69: 5193 5197.
98. Plano, L. R.,, D. M. Gutman,, M. Woischnik,, and C. M. Collins. 2000. Recombinant Staphylococcus aureus exfoliative toxins are not bacterial superantigens. Infect. Immun. 68: 3048 3052.
99. Pokorny, A.,, T. H. Birkbeck,, and P. F. Almeida. 2002. Mechanism and kinetics of delta-lysin interaction with phospholipid vesicles. Biochemistry 41: 11044 11056.
100. Prevost, G.,, P. Coupie,, P. Prevost,, S. Gayet,, P. Petiau,, B. Cribier,, H. Monteil,, and Y. Piemont. 1995. Epidemiological data on Staphylococcus aureus strains producing synergohymenotropic toxins. J. Med. Microbiol. 42: 237 245.
101. Prevost, G.,, B. Cribier,, P. Couppie,, P. Petiau,, G. Supersac,, V. Finck-Barbancon,, H. Monteil,, and Y. Piemont. 1995. Panton-Valentine leucocidin and gammahemolysin from Staphylococcus aureus ATCC 49775 are encoded by distinct genetic loci and have different biological activities. Infect. Immun. 63: 4121 4129.
102. Prevost, G.,, S. Rifai,, M. L. Chaix,, S. Meyer,, and Y. Piemont,. 1992. Is the His72, Asp120, Ser195 constitutive of the catalytic site of staphylococcal exfoliative toxin A? p. 488 489. In B. Witholt (ed.), Bacterial Protein Toxins. Fischer, Stuttgart, Germany.
103. Projan, S. J.,, J. Kornblum,, B. Kreiswirth,, S. L. Moghazeh,, W. Eisner,, and R. P. Novick. 1989. Nucleotide sequence: the β-hemolysin gene of Staphylococcus aureus. Nucleic Acids Res. 17: 3305.
104. Rago, J. V.,, G. M. Vath,, T. J. Tripp,, G. A. Bohach,, D. H. Ohlendorf,, and P. M. Schlievert. 2000. Staphylococcal exfoliative toxins cleave alpha- and beta-melanocyte-stimulating hormones. Infect. Immun. 68: 2366 2368.
105. Redpath, M. B.,, T. J. Foster,, and C. J. Bailey. 1991. The role of the serine protease active site in the mode of action of epidermolytic toxin of Staphylococcus aureus. FEMS Microbiol. Lett. 81: 151 156.
106. Reingold, A. L.,, N. T. Hargrett,, K. N. Shands,, B. B. Dan,, G. P. Schmid,, B. Y. Strickland,, and C. V. Broome. 1982. Toxic shock syndrome surveillance in the United States, 1980 to 1981. Ann. Intern. Med. 96: 875 880.
107. Ren, K.,, J. D. Bannan,, V. Pancholi,, A. L. Cheung,, J. C. Robbins,, V. A. Fischetti,, and J. B. Zabriskie. 1994. Characterization and biological properties of a new staphylococcal exotoxin. J. Exp. Med. 180: 1675 1683.
108. Rich, R. R.,, J. A. Mollick,, and R. G. Cook. 1989. Superantigens: interaction of staphylococcal enterotoxins with MHC class II molecules. Trans. Am. Clin. Climatol. Assoc. 101: 195 204.
109. Rogalsky, M. 1979. Nonenteric toxins of Staphyloccus aureus. Microbiol. Rev. 43: 320 360.
110. Sato, H.,, K. Hirose,, R. Terauchi,, S. Abe,, I. Moromizato,, S. Kurokawa,, and N. Maehara. 2004. Purification and characterization of a novel Staphylococcus chromogenes exfoliative toxin. J. Vet. Med. B Infect. Dis. Vet. Public Health 51: 116 122.
111. Scheuber, P. H.,, C. Denzlinger,, D. Wilker,, G. Beck,, D. Keppler,, and D. K. Hammer. 1987. Staphylococcal enterotoxin B as a nonimmunological mast cell stimulus in primates: the role of endogenous cysteinyl leukotrienes. Int. Arch. Allergy. Appl. Immunol. 82: 289 291.
112. Smith, T. P.,, D. A. John,, and C. J. Bailey. 1987. The binding of epidermolytic toxin from Staphylococcus aureus to mouse epidermal tissue. Histochem. J. 19: 137 149.
113. Smyth, D. S.,, P. J. Hartigan,, W. J. Meaney,, J. R. Fitzgerald,, C. F. Deobald,, G. A. Bohach,, and C. J. Smyth. 2005. Superantigen genes encoded by the egc cluster and SaPIbov are predominant among Staphylococcus aureus isolates from cows, goats, sheep, rabbits and poultry. J. Med. Microbiol. 54: 401 411.
114. Somerville, G. A.,, A. Cockayne,, M. Durr,, A. Peschel,, M. Otto,, and J. M. Musser. 2003. Synthesis and deformylation of Staphylococcus aureus delta-toxin are linked to tricarboxylic acid cycle activity. J. Bacteriol. 185: 6686 6694.
115. Song, L.,, M. R. Hobaugh,, C. Shustak,, S. Cheley,, H. Bayley,, and J. E. Gouaux. 1996. Structure of the staphylococcal α-hemolysin, a heptameric transmembrane pore. Science 274: 1859 1865.
116. Stohl, W.,, J. E. Elliott,, D. H. Lynch,, and P. A. Kiener. 1998. CD95 (Fas)-based, superantigen-dependent, CD4+ T cell-mediated down-regulation of human in vitro immunoglobulin responses. J. Immunol. 160: 5231 5238.
117. Sugawara, N.,, T. Tomita,, and Y. Kamio. 1997. Assembly of γ-hemolysin into a pore-forming ring-shaped complex on the surface of human erythrocytes. FEBS Lett. 410: 333 337.
118. Sugawara-Tomita, N.,, T. Tomita,, and Y. Kamio. 2002. Stochastic assembly of two-component staphylococcal gamma-hemolysin into heteroheptameric transmembrane pores with alternate subunit arrangements in ratios of 3:4 and 4:3. J. Bacteriol. 184: 4747 4756.
119. Sundstrom, M.,, L. Abrahmsen,, P. Antonsson,, K. Mehindate,, W. Mourad,, and M. Dohlsten. 1996. The crystal structure of staphylococcal enterotoxin type D reveals Zn 2+-mediated homodimerization. EMBO J. 15: 6832 6840.
120. Tappin, M. J.,, A. Pastore,, R. S. Norton,, J. H. Freer,, and I. D. Campbell. 1988. High-resolution 1H NMR study of the solution structure of δ-hemolysin. Biochemistry 27: 1643 1647.
121. Terauchi, R.,, H. Sato,, Y. Endo,, C. Aizawa,, and N. Maehara. 2003. Cloning of the gene coding for Staphylococcus intermedius exfoliative toxin and its expression in Escherichia coli. Vet. Microbiol. 94: 31 38.
122. Tiedemann, R. E.,, and J. D. Fraser. 1996. Cross-linking of MHC class II molecules by staphylococcal enterotoxin A is essential for antigen-presenting cell and T cell activation. J. Immunol. 157: 3958 3966.
123. Tomita, T.,, Y. Ueda,, H. Tamura,, R. Taguchi,, and H. Ikezawa. 1993. The role of acidic amino-acid residues in catalytic and adsorptive sites of Bacillus cereus sphingomyelinase. Biochim. Biophys. Acta 1203: 85 92.
124. Valeva, A.,, A. Weisser,, B. Walker,, M. Kehoe,, H. Bayley,, S. Bhakdi,, and M. Palmer. 1996. Molecular architecture of a toxin pore: a 15 residue sequence lines the transmembrane channel of staphylococcal alpha-toxin. EMBO J. 15: 1857 1864.
125. Vandenesch, F.,, T. Naimi,, M. C. Enright,, G. Lina,, G. R. Nimmo,, H. Heffernan,, N. Liassine,, M. Bes,, T. Greenland,, M. E. Reverdy,, and J. Etienne. 2003. Community-acquired methicillin-resistant Staphylococcus aureus carrying Panton-Valentine leukocidin genes: worldwide emergence. Emerg. Infect. Dis. 9: 978 984.
126. Vath, G. M.,, C. A. Earhart,, D. D. Monie,, J. J. Iandolo,, P. M. Schlievert,, and D. H. Ohlendorf. 1999. The crystal structure of exfoliative toxin B: a superantigen with enzymatic activity. Biochemistry 38: 10239 10246.
127. Vath, G. M.,, C. A. Earhart,, J. V. Rago,, M. H. Kim,, G. A. Bohach,, P. M. Schlievert,, and D. H. Ohlendorf. 1997. The structure of the superantigen exfoliative toxin A suggests a novel regulation as a serine protease. Biochemistry 36: 1559 1566.
128. von Eiff, C.,, R. A. Proctor,, and G. Peters. 2000. Small colony variants of staphylococci: a link to persistent infections. Berl. Munch. Tierarztl. Wochenschr. 113: 321 325.
129. Walev, I.,, U. Weller,, S. Strauch,, T. Foster,, and S. Bhakdi. 1996. Selective killing of human monocytes and cytokine release provoked by sphingomyelinase (beta toxin) of Staphylococcus aureus. Infect. Immun. 64: 2974 2979.
130. White, J.,, A. Herman,, A. M. Pullen,, R. Kubo,, J. W. Kappler,, and P. Marrack. 1989. The V beta-specific superantigen staphylococcal enterotoxin B: stimulation of mature T cells and clonal deletion in neonatal mice. Cell 56: 27 35.
131. Williams, R. E. O.,, and G. H. Harper. 1947. Staphylococcal haemolysins on sheep blood agar with evidence for a fourth haemolysin. J. Pathol. Bacteriol. 59: 69 78.
132. Williams, R. J.,, J. M. Ward,, B. Henderson,, S. Poole,, B. P. O’Hara,, M. Wilson,, S. P. Nair. 2000. Identification of a novel gene cluster encoding staphylococcal exotoxin-like proteins: characterization of the prototypic gene and its protein product, SET1. Infect. Immun. 68: 4407 4415.
133. Wiseman, G. M. 1975. The hemolysins of Staphylococcus aureus. Bacteriol. Rev. 39: 317 344.
134. Woodin, A. M., 1970. Staphylococcal leukocidin, p. 327 355. In T. C. Montie,, S. Kadis,, and S. J. Ajl (ed.), Microbial Toxins. Academic Press, New York, N.Y.
135. Yamaguchi, T.,, T. Hayashi,, H. Takami,, K. Nakasone,, M. Ohnishi,, K. Nakayama,, S. Yamada,, H. Komatsuzawa,, and M. Sugai. 2000. Phage conversion of exfoliative toxin A production in Staphylococcus aureus. Mol. Microbiol. 38: 694 705.
136. Yamaguchi, T.,, T. Hayashi,, H. Takami,, M. Ohnishi,, T. Murata,, K. Nakayama,, K. Asakawa,, M. Ohara,, H. Komatsuzawa,, and M. Sugai. 2001. Complete nucleotide sequence of a Staphylococcus aureus exfoliative toxin B plasmid and identification of a novel ADP-ribosyltransferase, EDIN-C. Infect. Immun. 69: 7760 7771.
137. Yamaguchi, T.,, K. Nishifuji,, M. Sasaki,, Y. Fudaba,, M. Aepfelbacher,, T. Takata,, M. Ohara,, H. Komatsuzawa,, M. Amagai,, and M. Sugai. 2002. Identification of the Staphylococcus aureus etd pathogenicity island which encodes a novel exfoliative toxin, ETD, and EDIN-B. Infect. Immun. 70: 5835 5845.
138. Yoshizawa, Y.,, J. Sakurada,, S. Sakurai,, K. Machida,, I. Kondo,, and S. Masuda. 2000. An exfoliative toxin A-converting phage isolated from Staphylococcus aureus strain ZM. Microbiol. Immunol. 44: 189 191.
139. Zhang, S.,, J. J. Iandolo,, and G. C. Stewart. 1998. The enterotoxin D plasmid of Staphylococcus aureus encodes a second enterotoxin determinant ( sej). FEMS Microbiol. Lett. 168: 227 233.
140. Zou, D.,, J. Kaneko,, S. Narita,, and Y. Kamio. 2000. Prophage,ϕPV83-pro, carrying panton-valentine leukocidin genes, on the Staphylococcus aureus P83 chromosome: comparative analysis of the genome structures of ϕPV83-pro, ϕPVL, ϕ11, and other phages. Biosci. Biotechnol. Biochem. 64: 2631 2643.


Generic image for table

Reported, confirmed, or potential staphylococcal PTSAgs

SE nomenclature used in this table is that recommended by the International Nomenclature Committee for Staphylococcal Superantigens ( ). Toxins either lacking activity or not yet tested for emetic activity in the primate oral feeding assay are designated staphylococcal enterotoxin-like toxins (SEls), according to standard nomenclature ( ).

ND, not determined or reported.

Weakly emetic ( ).


Originally designated SEK ( ).

Originally designated SEL ( ).

Originally designated SEM ( ).

T-cell stimulation reportedly results from Vα stimulation ( ).

Citation: Bohach G. 2006. Exotoxins, p 464-477. 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.ch38

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error