Toxin in bullous impetigo and staphylococcal scalded-skin syndrome targets desmoglein 1

Abstract

Exfoliative toxin A, produced by Staphylococcus aureus, causes blisters in bullous impetigo and its more generalized form, staphylococcal scalded-skin syndrome. The toxin shows exquisite specificity in causing loss of cell adhesion only in the superficial epidermis. Although exfoliative toxin A has the structure of a serine protease, a target protein has not been identified. Desmoglein (Dsg) 1, a desmosomal cadherin that mediates cell-cell adhesion, may be the target of exfoliative toxin A, because it is the target of autoantibodies in pemphigus foliaceus, in which blisters form with identical tissue specificity and histology. We show here that exfoliative toxin A cleaved mouse and human Dsg1, but not closely related cadherins such as Dsg3. We demonstrate this specific cleavage in cell culture, in neonatal mouse skin and with recombinant Dsg1, and conclude that Dsg1 is the specific receptor for exfoliative toxin A cleavage. This unique proteolytic attack on the desmosome causes a blister just below the stratum corneum, which forms the epidermal barrier, presumably allowing the bacteria in bullous impetigo to proliferate and spread beneath this barrier.

The Fate of Desmosomal Proteins in Apoptotic Cells

“…blistering skin disease. Recently the Staphlyococcus aureus exfoliative toxin A was shown to act as a protease cleaving the extracellular domain of Dsg1 and and to be responsible for the molecular pathology of the blistering diseases staphylococcal scalded skin syndrome and bullous impetigo (43).…”

150thAnniversary Series: Desmosomes and Autoimmune Disease, Perspective of Dynamic Desmosome Remodeling and Its Impairments in Pemphigus

“…The latter is caused by autoantibodies to Dsg1 and clinically characterized by very fragile superfi cial blisters and large leafy scales due to acantholysis at the granular cell layer in the epidermis, but not observed in the mucous membranes (Amagai, 1999;Stanley, 1993;. These different clinical features between PV and PF are well explained by the compensation theory of Dsg1 and Dsg3 (Mahoney et al, 1999;Amagai et al, 2000), which will be discussed later.…”

“…The mechanisms by which acantholysis occurs at the superfi cial, mostly granular, layers in PF and at the lower, typically along the suprabasal cell layers in PV, may be well explained by the compensation theory of Dsg1 and Dsg3 (Mahoney et al, 1999;Amagai et al, 2000). The antigen of pathogenic autoantibodies in PF, that is, only Dsg1, is expressed mainly in the upper epidermis, especially granular cell layer (Figure 3), whereas the essential and characteristic antigen of pathogenic antibodies in PV, that is, Dsg3, is much higher in the deep epidermis and much lower in the granular cell layer at protein levels ( Figure 3).…”

“…Although even the mucosal type of PV generates often in suprabasal or deeper epithelium, this may be due to a denser concentration of antibodies infi ltrated from the sub-mucosal tissue or a possibly functional expression of Dsg1 in upper epithelium of oral mucosa even with minimum expression. The latter group of PV patients, which is referred to muco-cutaneous type of PV, generates severe blistering, because functions of both Dsg1 and Dsg3 are affected/destroyed (Mahoney et al, 1999;Amagai et al, 2000).…”

Diagnostic dilemma: extremely low birth weight baby with staphylococcal scalded-skin syndrome or toxic epidermal necrolysis

“…Both ETA and ETB produce their effect by cleaving the cell adhesion molecule desmoglein1, which leads to the pathologic finding of cleavage of the mid-to upper level epidermis with cuboidal cells, large nuclei and no inflammatory cells. 1,2 The clinical features of SSSS were first described over a century ago but the disease received little attention until Lyell 3 described a skin eruption that resembled scalded skin and called it TEN. Lyell 3 later determined that exfoliation associated with S. aureus infection occurred within the epidermis whereas exfoliation not associated with staphylococcal infection occurred at the dermoepidermal junction; 4 the former condition was termed SSSS and the latter was termed TEN.…”