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Abstract
Staphylococcal scalded skin syndrome (SSSS) is a disease which is seen primarily in newborns and young children and is characterized by a bullous impetigo, scarlatinaform rash, and subsequently, a generalized exfoliation of surface layers of the epidermis. The name is derived from the scalded appearance of the skin of an infected individual. The disease is caused by the staphylococcal exfoliative toxins (ETs), namely, exfoliative toxin type A or type B (ETA or ETB). ETA is a 242 amino acid protein of 26,951Da in its mature form, while the mature ETB molecule is 246 amino acids in length and has a molecular weight of 27,318Da.
ETA appears to have few multiorgan effects on the host, but rather, is directed to the stratum gramilosum layer of the epidermis where the non-cytolytic, inter-cellular, intra-epidermal splitting characteristic of SSSS occurs. The recent solution of the three-dimensional structure of ETA shows a typical serine protease active site, which suggests the toxin may be acting as a specific serine protease in the epidermis. However, prior to this study, in vitro protease activity of ETA had not been conclusively demonstrated.
This study has shown that ETA possesses several biological activities which can be eliminated via site-directed mutagenesis. It has been shown that epidermolytic (exfoliative) activity can be eliminated by mutating residues located in the serine protease active site. These same mutants were also rendered to be incapable of cleaving an ester substrate in vitro, while epidermolytically active forms of ETA were still able to cleave this same substrate, which strongly suggests that some sort of site-specific serine protease catalysis may be involved in disease causation. While the exact target(s) for ETA in vivo has yet to be found, the 2.66 kDa peptide β-melanocyte stimulating hormone (β-MSH) has been shown to be susceptible to proteolytic cleavage by ETA. Moreover, a mutant that was epidermolytically and esterolytically inactive was unable to cleave this peptide.
These active site mutants were found to retain their wild type-like lymphocyte mitogenic activity, but several other mutants were found to be significantly deficient in their ability to act as mitogens. Some mutations in residues near the active site were found to have reduced lymphocyte mitogenic activity, but were still epidermolytically active, although some required higher concentrations of toxin to cause disease.
