Role of Staphylococcus aureus Global Regulators sae and σ ^B in Virulence Gene Expression during Device-Related Infection

Abstract

The ability of Staphylococcus aureus to adapt to different environments is due to a regulatory network comprising several loci. Here we present a detailed study of the interaction between the two global regulators sae and B of S. aureus and their influence on virulence gene expression in vitro, as well as during devicerelated infection. The expression of sae, asp23, hla, clfA, coa, and fnbA was determined in strain Newman and its isogenic saeS/R and sigB mutants by Northern analysis and LightCycler reverse transcription-PCR. There was no indication of direct cross talk between the two regulators. sae had a dominant effect on target gene expression during device-related infection.B seemed to be less active throughout the infection than under induced conditions in vitro.Staphylococcus aureus causes a variety of local and systemic infections in humans and is one of the most important community-acquired and nosocomial pathogens. Staphylococci are the most frequently implicated etiologic agents in device-related infections, in which the bacteria accumulate locally and often persist until the device is removed. Animal models using tissue cages as devices (37) allow the monitoring of various microbiological and immunological events during the course of infection.The ability of S. aureus to adapt to different environments is probably due to a global regulatory network comprising the loci agr, sar, sigB, rot, arlR/S, svrA, and saeR/S (1, 6-8, 28, 36). Each of these regulators is involved in the control of the expression of virulence factors such as hemolysins (for instance alpha-hemolysin, encoded by hla), protein A, fibronectin-binding proteins (FnBPA and FnBPB, encoded by fnbA and fnbB), or capsular polysaccharide (CP, encoded by the cap operon). Knowledge about the impact of these regulatory circuits on virulence gene expression during infection is still limited. In certain infections the central regulator agr is not involved in the activation of virulence factors (17,18,35). For instance in an experimental infective endocarditis model it was shown that fnbA is positively regulated in the absence of agr and sarA (34), suggesting additional regulatory loci in vivo. We could show that the regulator Sae is essential for the transcription of hla during device-related infection in guinea pigs (18). Recently, the importance of sae was shown in two whole-genome screens for the identification of genes required for full virulence (2, 3). The sae locus consists of four ORFs, two of which (saeR and saeS) show strong sequence homology to response regulators and histidine kinases of bacterial two-component regulators (12). Two additional ORFs, ORF3 and ORF4, located upstream of saeR/S are likely to be important for functionality of the sae operon (29, 31). Four overlapping sae-specific transcripts (T1 to T4) originate from three promoters (P1, P2, and P3): the T1 message (3.1 kb) initiates upstream of ORF4, T2 (2.4 kb) initiates upstream of ORF3, and T3 (2.0 kb) initiates in front of saeR (Fig. 1). T4 (0.7 kb) represents a monocis...

Transcriptional profiling of a Staphylococcus aureus clinical isolate and its isogenic agr and sarA mutants reveals global differences in comparison to the laboratory strain RN6390

“…higher levels in RN6390 in the absence of the additional regulatory influence of saeSR. This is also potentially important in that sae plays an important role in devicerelated infection (Goerke et al, 2005).…”

The Virulence Regulator Sae ofStaphylococcus aureus:Promoter Activities and Response to Phagocytosis-Related Signals

“…Microarray analysis and proteomics have revealed that most of the genes activated by sae are involved in bacterial adhesion, immune modulation, or toxicity (25,29,38). In addition, the importance of gene regulation by sae in vivo was shown in several animal models (3,15,16,29,43).The sae locus consists of four open reading frames, two of which (saeR and saeS) show strong sequence homology to response regulators and to histidine kinases (HKs) of bacterial two-component regulators (10). Two additional open reading frames, saeP and saeQ, both located upstream of saeRS, are likely to be important for the functionality of the sae operon (33, 39).…”

Identification of the P3 Promoter and Distinct Roles of the Two Promoters of the SaeRS Two-Component System in Staphylococcus aureus

“…Among the 16 TCSs in S. aureus, the SaeRS TCS plays a key regulatory role in the production of important virulence factors, such as coagulase (Coa), alpha-hemolysin (Hla), and fibronectin binding proteins (14,16,27,34,46). The TCS has been shown to contribute to in vivo survival of the bacterium and to the apoptosis of lung epithelial cells (27,44).…”