Abstract
Two epidermolytic toxins, produced by different strains of Staphylococcus aureus, split human skin at a site in the upper epidermis. Clinical effects are most common in infants, but adults are susceptible. Epidermolysis may also be observed in the mouse, in vivo and in vitro, and in a few other mammals. Recent in vitro experiments have demonstrated an inhibition by chelators and point to metal-ion, possibly Ca2+, involvement. The epidermolysis effect is insensitive to a wide range of other metabolic inhibitors. The toxin amino acid sequences are similar to that of staphylococcal proteinase, and new experiments by chemical modification and site-directed mutagenesis have shown that toxicity depends on ‘active serine’ residues of a catalytic triad similar to that found in serine proteases. Furthermore the toxins possess esterolytic activity, also dependent on the ‘active serine’ sites. However, the toxins have low or undetectable activity towards a range of peptide or protein substrates. In histological and related studies, the toxins bound selectively to an intracellular skin protein, profilaggrin, but there was no evidence that the toxin can enter intact epidermal cells. Therefore, although the circumstantial evidence that the toxins act by proteolysis is convincing, a specific skin proteolytic substrate for the toxin has not been identified.
Similar content being viewed by others
References
Arbuthnott JP, Kent J, Lyell A, Gemmell CG (1971) Toxic Epidermal necrolysis produced by an extracellular product of Staphylococcus aureus. Br J Dermatol 85:145–149
Arbuthnott JP, Kent J, Noble WC (1973) The response of hairless mice to Staphylococcal epidermolytic toxin. Br J Dermatol 88:481–485
Baker DH, Dimond RL, Wuepper KD (1978) The epidermolytic toxin of S. aureus. Its failure to bind to cells and its detection in blister fluids of patients with Bullous impetigo. J Invest Dermatol 71:274–275
Bailey CJ, Redpath MB (1992) The esterolytic activity of epidermolytic toxins. Biochem J 284:177–180
Bailey CJ, Smith TP (1990) The reactive serine of epidermolytic toxin A. Biochem J 269:535–537
Bailey CJ, de Azavedo J, Arbuthnott JP (1980) A comparative study of two serotypes of epidermolytic toxin from Staphylococcus aureus. Biochem Biophys Acta 624:111–120
Bailey CJ, Martin SR, Bayley PM (1982) A circular dichroism study of epidermolytic toxins A & B from Staphylococcus aureus. Biochem J 203:775–778
Bhakdi S, Grimminger F, Suttorp N, Walmrath D, Seeger W (1994) Proteinaceous bacterial toxins and pathogenesis of sepsin syndrome and septic shock: the unknown connection. Med Microbiol Immunol 180:273–278
Buxton RS, et al. (1993) Nomenclature of the desmosomal cadherins. J Cell Biol 121:481–483
Chen F-S, Melish ME (1982) Demonstration of staphylococcal epidermolytic toxin receptors in human and murine skin. Fed Proc 41:139
Dancer SJ, Garratt R, Saldanha J, Jhoti H, Evans R (1990) The epidermolytic toxins are serine proteases. FEBS Lett 268:129–132
Dancer SJ, Poston SM, East J, Simmons MA, Noble WC (1990) An outbreak of pemphigous neonatorum. J Infect 20:73–82
Dave J, Reith S, Nash JQ, Marples RR, Dulake C (1994) A double outbreak of exfoliative toxin-producing strains of Staphylococcus aureus in a maternity unit. Epidemiol Infect 112:103–114
De Azavedo JCS, Arbuthnott JP (1988) Assays for epidermolytic toxin of Staphylococcus aureus. Method Enzymol 165:333–338
Dimond RL, Wuepper KD (1976) Purification and characterisation of a staphylococcal epidermolytic toxin. Infect Immun 13:627–633
Drapeau GR (1978) The primary structure of staphylococcal protease. Can J Biochem 56:534–544
Elias PM, Fritsch P, Tappeiner G, Mittermayer H, Wolff K (1974) Experimental Staphylococcal toxic epidermal necrolysis (TEN) in adult humans and mice. J Lab Clin Med 84:414–424
Elias PM, Fritsch P, Mittermeyer H (1976) Staphyococcal toxic epidermal necrolysis: species and tissue susceptibility and resistance. J Invest Dermatol 66:80–89
Elias PM, Fritsch P, Epstein EH (1977) Staphylococcal scalded skin syndrome. Arch Dermatol 113:207–219
Elsner P, Hartman AA, Lenz W, Brandis H (1985) Screening of clinical S aureus isolates for the production of exfoliative toxin. Zentrabl Bakteriol Mikrobiol Hyg 260:216–220
Fleischer B, Bailey CJ (1992) Recombinant epidermolytic (exfoliative) toxin A of Staphylococcus aureus is not a superantigen. Med Microbiol Immunol 180:273–278
Freer J, Arbuthnott JP (1983) Toxins of Staphylococcus aureus. Pharmacol Therapeut 19:55–106
Freinkel RK, Traczyk TN (1981) A method for partial purification of lamellar granules from fetal rat epidermis. J Invest Dermatol 77:478–482
Fritsch P, Elias PM, Varga J (1976) The fate of Staphylococcal exfoliatin in newborn and adult mice. Br J Dermatol 95:275–284
Fritsch PO, Kaasaver G, Elias PM (1979) Action of staphylococcal epidermolysin: further observations on its species specificity. Archs Dermatol Res 264:287–291
Gentilhomme E, Faure M, Binder P, Thivolet J (1990) Action of staphylococcal exfoliative toxins on epidermal cell cultures and organotypic skin. J Dermatol 17:526–532
Gray SG, Kehoe M (1984)Primary structure of the a-toxin gene from Staphylococcus aureus. Infect Immun 46:615–618
Grayson S, Johnson-Winegar AG, Wintroub BU, Isserott RR, Epstein EH, Elias PM (1984) Lamellar body-enriched fractions from neonatal mice:preparative techniques and partial characterisation. J Invest Dermatol 85:289–299
Herman A, Kappler JM, Marrack P, Pullen AM (1990) Superantigens:mechanism of T cell stimulation and role in immune response. Annu Rev Immunol 9:745–772
Inaoki M (1990) Experimental studies on the mechanism of action of Staphylococcal epidermolytic toxin A utilizing recombinant toxin. Nippon Hituka Gakkai Zasshi 100:1405–1414
Jackson MP, Iandolo JJ (1986) Sequence of the exfoliative toxin B gene of Staphylococcus aureus. J Bacteriol 167:574–580
Johnson AD, Metzgen JF, Spero L (1975) Productive purification and Chemical characterisation of Staphylococcus aureus exfoliative toxin. Infect Immun 12:1206–1210
Johnson AD, Spero L, Cades JS, De Cicco BT (1979) Purification and characterisation of different types of exfoliative toxin from Staphylococcus aureus. Infect Immun 24:679–684
Kaplan MH, Chmel H, Hsieh HC, Stephens A, Brinsko V (1986) Importance of exfoliatin A production by Staphylococcus aureus strains isolated from clustered epidemics of neonatal pustulosis. J Clin Microbiol 23:83–91
Kapral FA, Miller MM (1971) Product of Staphylococcus aureus responsible for the scalded-skin syndrome. Infect Immun 4:541–545
Kondo I, Sakurai S, Sari Y (1976) Staphylococcal exfoliation A and B. In: Jeljaszewicz J (ed) Staphylococci and staphylococcal diseases. Gustav Fischer, Stuttgart, pp 489–498
Lee CY, Schmidt JJ, Johnson-Winegar AD, Spero L, Iandolo JJ (1987) Sequence determination and comparison of the exfoliative toxin A and toxin B genes from Staphylococcus aureus. J Bacteriol 169:3904–3909
Lillibridge CB, Melish ME, Glasgow LA (1972) Site of action of exfoliative toxin in the staphylococcal scalded-skin syndrome. Pediatrics 50:728–738
Lockhart BP, Bailey CJ (1993) ELISA estimation of the binding of epidermolytic toxin to neonatal mouse skin. Toxicon 31:569–576
Lockhart BP, Smith TP, Bailey CJ (1991) Immunofluorescence localization of the epidermolytic toxin target in mouse epidermal cells and tissue. Histochem J 23:385–391
Lyell A (1979) Toxic epidermal necrolysis (the scalded skin syndrome: a reappraisal). Br J Dermatol 100:69–86
McCallum HM (1972) Action of staphylococcal epidermolytic toxin on mouse skin in organ culture. Br J Dermatol 86 [Suppl 8]:40–41
McLay ALC, Arbuthnott JP, Lyell A (1975) Action of Staphylococcal epidermolytic toxin on mouse skin: an electron microscopic study. J Invest Derm 65:423–428
Melish ME, Glasgow LA (1970) The staphylococcal scalded skin syndrome: Development of an experimental model. N Engl J Med 282:1114–1119
Melish ME, Glasgow LA (1971) Staphylococcal scalded skin syndrome: the expanded clinical syndrome. J Pediatr 78:958–967
Melish ME, Chen FS, Sprouse S, Stuckey M, Murata MS (1981) Epidermolytic toxin in Staphylococcal infection: toxin levels and host response. In: Jeljaszewicz J (ed) Staphylococci and staphylococcal infections. Fischer, Stuttgart, pp 287–298
Nishioka K, Katayama I, Sano S (1981) Possible binding of epidermolytic toxin to a subcellular fraction of the epidermis. J Dermatol 8:7–12
Opal SM, Johnston-Winegar AD, Cross AS (1988) Staphylococcal scalded skin syndrome in two immunocompetent adults caused by exfoliation B-producing Staphylococcus aureus. J Clin Microbiiol 26:1283–1286
O'Toole P, Foster TJ (1986) Molecular cloning and expression of the epidermolytic toxin A gene of Staphylococcus aureus. Microbial Pathogenesis 1:583–594
O'Toole PW, Foster TJ (1987) Nucleotide sequence of the Epidermolytic Toxin A gene of Staphylococcus aureus. J Bacteriol 169:3910–3915
Prévost G, Rifai S, Chaix ML, Piédmont Y (1991) Functional evidence that the Ser-195 residue of staphylococcal exfoliative toxin A is essential for biological activity. Infect Immun 59:3337–3339
Prévost G, Rifai S, Chaix ML, Meyer S, Piédmont Y (1992) Is the His72, Asp120, Ser195 triad constitutive of the catalytic site of staphylococcal exfoliative toxin A? In: Witholt B et al. (eds) Bacterial protein toxins. Fischer, Stuttgart, pp 488–489
Redpath MB, Foster TJ, Bailey CJ (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
Sakurai S, Kondo I (1978) Characterisation of staphylococcal exfoliatin A as a metallotoxin with special reference to determination of the contained metal by radioactivation analysis. Jpn J Med Sci Biol 31:208–211
Sakurai S, Suzaki H, Kondo I (1988) DNA sequencing of the eta gene coding for staphylococcal exfoliatin toxin serotype A. J Gen Microbiol 134:711–717
Sato H, Kuramato M, Tanabe T, Saito H (1991) Susceptibility of various animals and cultured cells to exfoliative toxin produced by Staphylococcus hyicus subsp.-hyicus. Vet Microbiol 28:157–169
Sheehan BJ, Foster TJ, Dorman CJ, Park S, Stewart GSAB (1992) Osmotic and growth-phase dependent regulation of the etagene of Staphylococcus aureus: a role for DNA supercoiling. Mol Gen Genet 232:49–57
Skerrow CJ (1980) The experimental production of high-level intraepidermal splits. Br J Dermatol 102:75–83
Smith TP, Bailey CJ (1986) Epidermolytic toxin from Staphylococcus aureus binds to filaggrins. FEBS Lett 194:309–312
Smith TP, Bailey CJ (1990) Activity requirements of epidermolytic toxin from Staphylococcus aureus studied by an in vitro assay. Toxicon 28:675–683
Smith TP, John DA, Bailey CJ (1987) The binding of epidermolytic toxin from Staphylococcus aureus to mouse epidermal tissue. Histochem J 19:137–149
Smith TP, John DA, Bailey CJ (1989) Epidermolytic toxin binds to components in the epidermis of a resistant species. Eur J Cell Biol 49:341–149
Stanley JR (1989) Pemphigus and Pemphigoid as paradigms of organ-specific autoantibody-mediated diseases. J Clin Invest 83:1443–1448
Stephen J, Pietrowski RA (1986) Bacterial toxins. American Society for Microbiology, Washington, pp 8–10
Tanabe T, Sato H, Kuramato M, Saito H (1993) Purification of exfoliative toxin produced by Staphylococcus hyicus and its antigenicity. Infect Immun 61:2973–2977
Uhlen M, guss B, Nilsson B, Grantenbeck S, Philipson L, Lindberg M (1984) Complete sequence of the staphylococcal gene encoding protein A. J Biol Chem 259:1695–1702
Wuepper KD, Dimond RL, Knutson DD (1975) Studies in the mechanism of epidermal injury on Staphylococcal epidermolytic toxin. J Invest Dermatol 65:191–200
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Bailey, C.J., Lockhart, B.P., Redpath, M.B. et al. The epidermolytic (exfoliative) toxins of Staphylococcus aureus . Med Microbiol Immunol 184, 53–61 (1995). https://doi.org/10.1007/BF00221387
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00221387