Staphylococcus epidermidis saeR Is an Effector of Anaerobic Growth and a Mediator of Acute Inflammation

Abstract

The saeRS two-component regulatory system regulates transcription of multiple virulence factors in Staphylococcus aureus. In the present study, we demonstrated that the saePQRS region in Staphylococcus epidermidis is transcriptionally regulated in a temporal manner and is arranged in a manner similar to that previously described for S. aureus. Studies using a mouse foreign body infection model demonstrated that the virulence of strain 1457 and the virulence of a mutant, strain 1457 saeR, were statistically equivalent. However, histological analyses suggested that the polymorphonuclear neutrophil response at 2 days postinfection was significantly greater in 1457-infected mice than in 1457 saeR-infected mice, demonstrating that SaeR influences the early, acute phases of infection. Microarray analysis demonstrated that a saeR mutation affected the transcription of 65 genes (37 genes were upregulated and 28 genes were downregulated); in particular, 8 genes that facilitate growth under anaerobic conditions were downregulated in 1457 saeR. Analysis of growth under anaerobic conditions demonstrated that 1457 saeR had a decreased growth rate compared to 1457. Further metabolic experiments demonstrated that 1457 saeR had a reduced capacity to utilize nitrate as a terminal electron acceptor and exhibited increased production of lactic acid in comparison to 1457. These data suggest that in S. epidermidis SaeR functions to regulate the transition between aerobic growth and anaerobic growth. In addition, when grown anaerobically, 1457 saeR appeared to compensate for the redox imbalance created by the lack of electron transport-mediated oxidation of NADH to NAD ؉ by increasing lactate dehydrogenase activity and the subsequent oxidation of NADH.

Staphylococcus aureus Nuclease Is an SaeRS-Dependent Virulence Factor

“…While Nuc enzyme levels are known to be higher in sarA and sigB mutants (9), it is often stated in the S. aureus literature that production of Nuc is under agr quorumsensing system control because diminished Nuc activity was observed in agr-defective strains (11)(12)(13). However, multiple reports have provided preliminary observations that Nuc is actually regulated by SaeRS, a two-component system responsible for the production of a diverse array of secreted toxins, immunomodulators, and enzymes (14)(15)(16)(17). Initial proteomic and microarray observations were reported by Rogasch et al (17) that demonstrated the influence of saeS on Nuc expression in strains COL and Newman, and we made similar observations through microarray analysis of CA MRSA saeRS deletion mutants (14,15).…”

“…5). Even though this strain was isolated from an endocarditis patient, 18805 has been shown to be attenuated in a model of invasive infection (16), which sup- 7 CFU of WT USA300 or isogenic agr, sae, and nuc mutants. Nuc activity in peritoneal fluids was assayed at 8 h postinfection with a FRET assay (n ϭ 5 mice per strain for the WT and the agr and sae mutants and 4 mice for the nuc mutant).…”

The SaeRS Two‐Component System of Staphylococcus aureus

“…None of those virulence genes are found in the closely related S. epidermidis , which also has the SaeRS TCS [136,137]. Therefore, S. aureus seems to have evolved its virulence capacity by acquiring those virulence genes and placing them under the control of the SaeRS TCS.…”

Comparative Transcriptomics Reveals Discrete Survival Responses of S. aureus and S. epidermidis to Sapienic Acid

“…The saeRS operon homologs in S. epidermidis (SETU_00325 and SETU_00326, respectively) were not differentially expressed in response to sapienic acid. Moreover, genes of the S. epidermidis SaeRS regulon (Handke et al, 2008) did not show any particular expression pattern that would suggest this regulon was modulated. On this basis, we propose that SaeRS is not a key regulator of the sapienic acid survival response of S. epidermidis .…”