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SarZ is a key regulator of biofilm formation and virulence in Staphylococcus epidermidis

ABSTRACT: Biofilm-associated infection by the leading nosocomial pathogen Staphylococcus epidermidis is a major problem for the public health system. Here we used an especially discriminatory, two-step screen to discover key biofilm factors. We identified the transcriptional regulator and SarA paralog SarZ as a novel important determinant of biofilm formation and biofilm-associated infection by S. epidermidis. Notably, a sarZ mutant strain exhibited significantly reduced survival in two different models of biofilm-associated infection. Further, in addition to its significant influence on the transcription of the biosynthetic operon for S. epidermidis biofilm exopolysaccharide, sarZ impacted the expression of a series of virulence factors, including lipases and proteases. As a likely consequence of the regulated proteolytic activity, we observed increased resistance to an important human antimicrobial peptide, indicating a role for sarZ in the regulation of immune evasion. Interestingly, sarZ deficiency led to a hemolytic phenotype, a feature not commonly observed in S. epidermidis. Thus, our study indicates a key role for the SarZ regulator in maintaining the typical S. epidermidis phenotype, which is characterized by pronounced biofilm formation, immune evasion, and suppressed acute virulence, a likely reason for the success of S. epidermidis as a colonizer and pathogen in chronic, biofilm-associated infection. Keywords: Wild type control vs mutant

ORGANISM(S): Staphylococcus epidermidis RP62A Rickettsia rickettsii Chlamydia pneumoniae AR39 Coxiella burnetii RSA 493 Granulibacter bethesdensis Staphylococcus epidermidis Staphylococcus epidermidis ATCC 12228 Coxiella burnetii Chlamydia muridarum Chlamydia trachomatis D/UW-3/CX Staphylococcus haemolyticus JCSC1435 Borreliella burgdorferi B31 Staphylococcus aureus subsp. aureus MW2 Chlamydia caviae GPIC

PROVIDER: GSE8523 | GEO | 2008/07/16

SECONDARY ACCESSION(S): PRJNA101647

REPOSITORIES: GEO

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Project description:Staphylococcus epidermidis (SE) is one of the most common bacteria of the human skin microbiota. Despite its role as a commensal, SE has emerged as an opportunistic pathogen, associated with 80% of medical devices related infections. Moreover, these bacteria are extremely difficult to treat due to their ability to form biofilms and accumulate resistance to almost all classes of antimicrobials developed so far. Thus new preventive and therapeutic strategies are urgently needed. In spite of its clinical importance, the molecular mechanisms associated with SE colonisation and disease are still poorly understood. A deeper understanding of the metabolic and cellular processes associated with response to environmental factors characteristic of SE ecological niches in health and disease might provide new clues on colonisation and disease processes. Here we studied the impact of pH conditions, mimicking the skin pH (5.5) and blood pH (7.4), in a S. epidermidis commensal strain, belonging to the B clonal lineage, by means of next-generation proteomics and 1H NMR-based metabolomics. Moreover, we evaluated the metabolic changes occurring when a sudden pH change arise, simulating the skin barrier break produced by a catheter. We found that exposure of S. epidermidis to skin pH induced oxidative phosphorylation and biosynthesis of peptidoglycan, lipoteichoic acids and betaine. In contrast, at blood pH, the incorporation of monosaccharides and its oxidation by glycolysis and fermentation was promoted. Additionally, several proteins related to virulence and immune evasion, namely extracellular proteases and membrane iron transporters were more abundant at blood pH. In the situation of an abrupt skin-to-blood pH shift we observed the decrease in the osmolyte betaine and changes in the levels of several metabolites and proteins involved in redox cell homeostasis. Our results suggest that at the skin pH S. epidermidis cells are metabolically more active and adhesion is promoted, while at blood pH, metabolism is tuned down and cells have a more virulent profile. pH increase during commensal-to-pathogen conversion appears to be a critical environmental signal to the remodelling of the S. epidermidis metabolism towards a more pathogenic state. Targeting S. epidermidis proteins induced by a low alkaline pH and local acidification of medical devices microenvironment might be new strategies to treat and prevent S. epidermidis infections.

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SarZ is a key regulator of biofilm formation and virulence in Staphylococcus epidermidis

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