Regulatory mechanism for exfoliative toxin production in Staphylococcus aureus

The exfoliative toxin (ET) is a major virulence factor of Staphylococcus aureus that causes bullous impetigo and its disseminated form, staphylococcal scalded-skin syndrome (SSSS). ET selectively digests one of the intracellular adhesion molecules, desmoglein 1, of epidermal keratinocytes and causes blisters due to intraepidermal cell-cell dissociation. Most S. aureus strains that cause blistering disease produce either ETA or ETB. They are serologically distinct molecules, where ETA is encoded on a phage genome and ETB is enocded on a large plasmid. ETA-producing S. aureus strains are frequently isolated from impetigo patients, and ETB-producing S. aureus strains are isolated from SSSS. ET-induced blister formation can be reproduced with the neonatal mouse. To determine the regulatory mechanism of ET production, we investigated the role of the two-component systems and global regulators for eta or etb expression in vitro and in vivo with the mouse model. Western blot and transcription analyses using a series of mutants demonstrate ETA production was downregulated by sigB, sarS, and sarA, while ETB production was downregulated by sigB and sarA but not by sarS. Production of both toxins is upregulated by saeRS, arlRS, and agrCA. Furthermore, by the in vivo neonatal mouse model, sigB and sarS but not sarA negatively regulate the exfoliation activity of the ETA-producing strain, while sarA negatively regulates the ETB-producing strain. In both strains, saeRS, arlRS, and agrCA positively regulate the exfoliation activity in vivo. The data illustrate similar but distinct regulatory mechanisms for ETA and ETB production in S. aureus in vitro as well as in vivo.