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Infection and Immunity, October 2002, p. 5835-5845, Vol. 70, No. 10
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.10.5835-5845.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Identification of the Staphylococcus aureus etd Pathogenicity Island Which Encodes a Novel Exfoliative Toxin, ETD, and EDIN-B

Takayuki Yamaguchi,1 Koji Nishifuji,2 Megumi Sasaki,3 Yasuyuki Fudaba,1 Martin Aepfelbacher,4 Takashi Takata,5 Masaru Ohara,1 Hitoshi Komatsuzawa,1 Masayuki Amagai,2 and Motoyuki Sugai1*

Departments of Bacteriology,1 Oral Maxillofacial Pathobiology, Hiroshima University Graduate School of Biomedical Sciences, Kasumi 1-2-3, Minami-ku Hiroshima, Hiroshima 734-8553,5 Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582,2 Clinical Laboratory, Hiroshima City Hospital, 7-33 Motomachi, Hiroshima, Hiroshima 730-8518, Japan,3 Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, LMU Munich, 80336 Munich, Germany4

Received 26 February 2002/ Returned for modification 7 May 2002/ Accepted 25 June 2002

We identified a novel pathogenicity island in Staphylococcus aureus which contains open reading frames (ORFs) similar to the exfoliative toxin (ET) gene, glutamyl endopeptidase gene, and edin-B gene in tandem and the phage resistance gene, flanked by hsdM, hsdS (restriction and modification system), and IS256. The protein encoded by the ET-like gene showed 40, 59, and 68% amino acid sequence identities with exfoliative toxin A (ETA), exfoliative toxin B (ETB), and Staphylococcus hyicus ETB (ShETB), respectively. When injected into neonatal mice, the recombinant protein derived from the ET-like gene induced exfoliation of the skin with loss of cell-to-cell adhesion in the upper part of the epidermis as observed in histological examinations, just as was found in neonatal mice injected with ETA or ETB. Western blot analysis indicated that the recombinant protein is serologically distinct from ETA and ETB. Therefore, the product encoded by this new ORF is a new ET member produced by S. aureus and is termed ETD. ETD did not induce blisters in 1-day-old chickens. In the skins of mice injected with ETD, cell surface staining of desmoglein 1 (Dsg1), a cadherin type cell-to-cell adhesion molecule in desmosomes, was abolished without affecting that of desmoglein 3 (Dsg3). Furthermore, in vitro incubation of the recombinant extracellular domains of Dsg1 and Dsg3 with the recombinant protein demonstrated that both mouse and human Dsg1, but not Dsg3, were directly cleaved in a dose-dependent manner. These results demonstrate that ETD and ETA induce blister formation by identical pathophysiological mechanisms. Clinical strains positive for edin-B were suggested to be clonally associated, and all edin-B-positive strains tested were positive for etd. Among 18 etd-positive strains, 12 produced ETD extracellularly. Interestingly, these strains are mainly isolated from other sources of infections and not from patients with bullous impetigo or staphylococcal scalded-skin syndrome. This strongly suggests that ETD might play a pathogenic role in a broader spectrum of bacterial infections than previously considered.

* Corresponding author. Mailing address: Department of Bacteriology, Hiroshima University Graduate School of Biomedical Sciences, Kasumi 1-2-3, Minami-ku, Hiroshima City, Hiroshima 734-8553, Japan. Phone: (81) 82 257 5635. Fax: (81) 82 257 5639. E-mail: sugai{at}hiroshima-u.ac.jp.

Editor: V. J. DiRita

Infection and Immunity, October 2002, p. 5835-5845, Vol. 70, No. 10
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.10.5835-5845.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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