Molecular mechanisms of blister formation in bullous impetigo and staphylococcal scalded skin syndrome.
Bullous impetigo due to Staphylococcus aureus is one of the most common bacterial infections of man, and its generalized form, staphylococcal scalded skin syndrome (SSSS), is a frequent manifestation of staphylococcal epidemics in neonatal nurseries. Both diseases are mediated by exfoliative toxins (ETs), which show exquisite pathologic specificity in blistering only the superficial epidermis. We show that these toxins act as serine proteases with extremely focused molecular specificity to cleave mouse and human desmoglein 1 (Dsg1) once after glutamic acid residue 381 between extracellular domains 3 and 4. Mutation of the predicted catalytically active serine to alanine completely inhibits cleavage. The mutated ETs bind specifically to Dsg1 by immunofluorescence colocalization and by coimmunoprecipitation. Thus, ETs, through specific recognition and proteolytic cleavage of one structurally critical peptide bond in an adhesion molecule, cause its dysfunction and allow S. aureus to spread under the stratum corneum, the main barrier of the skin, explaining how, although they circulate through the entire body in SSSS, they cause pathology only in the superficial epidermis.
Hanakawa
Yasushi
Y
Department of Dermatology, University of Pennsylvania School of Medicine, 415 Curie Boulevard, Philadelphia, PA 19104, USA.
Schechter
Norman M
NM
Lin
Chenyan
C
Garza
Luis
L
Li
Hong
H
Yamaguchi
Takayuki
T
Fudaba
Yasuyuki
Y
Nishifuji
Koji
K
Sugai
Motoyuki
M
Amagai
Masayuki
M
Stanley
John R
JR
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001768:Blister / Q000209:etiology*; D015820:Cadherins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051183:Desmoglein 1; D005083:Exfoliatins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D007169:Impetigo / Q000209:etiology*; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D017386:Sequence Homology, Amino Acid; D013206:Staphylococcal Scalded Skin Syndrome / Q000209:etiology*
D015820:Cadherins; D051183:Desmoglein 1; D005083:Exfoliatins; D011994:Recombinant Proteins