Regulatory Mechanism for Exfoliative Toxin Production in Staphylococcus aureus

The exfoliative toxin (ET) is a major virulence factor ofStaphylococcus 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. MostS. 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-producingS. aureus strains are frequently isolated from impetigo patients, and ETB-producingS. 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 foreta oretb expressionin vitro andin vivo with the mouse model. Western blot and transcription analyses using a series of mutants demonstrate ETA production was downregulated bysigB ,sarS , andsarA , while ETB production was downregulated bysigB andsarA but not bysarS . Production of both toxins is upregulated bysaeRS ,arlRS , andagrCA . Furthermore, by thein vivo neonatal mouse model,sigB andsarS but notsarA negatively regulate the exfoliation activity of the ETA-producing strain, whilesarA negatively regulates the ETB-producing strain. In both strains,saeRS ,arlRS , andagrCA positively regulate the exfoliation activityin vivo . The data illustrate similar but distinct regulatory mechanisms for ETA and ETB productionin S. aureus in vitro as well asin vivo .