SaeRS Is Responsive to Cellular Respiratory Status and Regulates Fermentative Biofilm Formation in Staphylococcus aureus

Abstract

Biofilms are multicellular communities of microorganisms living as a quorum rather than as individual cells. The bacterial human pathogen Staphylococcus aureus uses oxygen as a terminal electron acceptor during respiration. Infected human tissues are hypoxic or anoxic. We recently reported that impaired respiration elicits a programmed cell lysis (PCL) phenomenon in S. aureus leading to the release of cellular polymers that are utilized to form biofilms. PCL is dependent upon the AtlA murein hydrolase and is regulated, in part, by the SrrAB two-component regulatory system (TCRS). In the current study, we report that the SaeRS TCRS also governs fermentative biofilm formation by positively influencing AtlA activity. The SaeRSmodulated factor fibronectin-binding protein A (FnBPA) also contributed to the fermentative biofilm formation phenotype. SaeRS-dependent biofilm formation occurred in response to changes in cellular respiratory status. Genetic evidence presented suggests that a high cellular titer of phosphorylated SaeR is required for biofilm formation. Epistasis analyses found that SaeRS and SrrAB influence biofilm formation independently of one another. Analyses using a mouse model of orthopedic implant-associated biofilm formation found that both SaeRS and SrrAB govern host colonization. Of these two TCRSs, SrrAB was the dominant system driving biofilm formation in vivo. We propose a model wherein impaired cellular respiration stimulates SaeRS via an as yet undefined signal molecule(s), resulting in increasing expression of AtlA and FnBPA and biofilm formation.

A Systematic Evaluation of the Two-Component Systems Network Reveals That ArlRS Is a Key Regulator of Catheter Colonization by Staphylococcus aureus

“…Because the levels of the PNAG exopolysaccharide produced in vitro were similar between the wild type and agr mutant strains, it is likely that PNAG is not involved in the decreased colonization capacity of the agr mutant in vivo . On the other hand, SrrAB has been shown to induce biofilm formation under anaerobic conditions through activation of icaADBC gene transcription ( Ulrich et al, 2007 ; Wu et al, 2015 ) and release of extracellular DNA ( Mashruwala et al, 2017 ). Since implanted catheters are thought to comprise anaerobic microenvironments, it might be possible that the srrA mutant has a catheter colonization deficiency because of a defect linked to oxygen sensing.…”

Interplay of Nitric Oxide Synthase (NOS) and SrrAB in Modulation of Staphylococcus aureus Metabolism and Virulence

“…8E). Strains with a mutation of srrAB have shown reduced virulence in anoxic sites, as in murine orthopedic implant-associated infections (41) and in intraosseous infections (22). S. aureus virulence in a murine septic arthritic model was highly influenced by SrrAB in both the presence and the absence of host nitrosative stress (18).…”

Staphylococcus aureus Responds to the Central Metabolite Pyruvate To Regulate Virulence

“…An additional regulatory system that is critical to S. aureus host adaptation is the S. aureus exoprotein (Sae) TCS ( 15 ). In response to low pH, changes in cellular respiration, high concentrations of sodium chloride, neutrophils and their contents, or subinhibitory levels of select antibiotics ( 16 – 19 ), the SaeS sensor kinase activates the SaeR response regulator, which directly modulates virulence gene expression. In the context of virulence factor regulation, particularly for the leucocidins, SaeR serves as the master activator of toxin expression.…”