The two-component system ArlS-ArlR is a regulator of virulence gene expression in Staphylococcus aureus

Staphylococcus aureus is a major human pathogen that produces many virulenc e factors in a temporally regulated manner controlled by at least two globa l virulence regulatory loci (agr and sarA). We identified previously a two- component system, ArIS-ArIR, that modifies the activity of extracellular se rine protease and may be involved in virulence regulation. Here, we show th at mutations in either arIR or arIS increase the production of secreted pro teins [alpha -toxin (Hla), beta -haemolysin, lipase, coagulase, serine prot ease (Ssp)] and especially protein A (Spa). Furthermore, the pattern of pro teins secreted by both mutants was strikingly different from that of the wi ld-type strain. Transcriptional fusions showed that expression of hla, ssp and spa was higher in both mutants than in the wild-type strain, indicating that the arl operon decreases the production of virulence factors by downr egulating the transcription of their genes. The arl mutation did not change spa expression in an agrA mutant or in a sarA mutant, suggesting that both the sarA and the agr loci are required for the action of arl on spa. North ern blot analyses indicated that the arl mutation increased the synthesis o f both RNA II and RNA III, but decreased sarA transcription. Finally, arl w as not autoregulated, but its expression was stimulated by agr and sarA. Th ese results suggest that the Arl system interacts with both agr and sarA re gulatory loci to modulate the virulence regulation network.