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Role of the LytSR two-component regulatory system in Staphylococcus lugdunensis biofilm formation and pathogenesis

ABSTRACT: Staphylococcus lugdunensis is a coagulase negative Staphylococcus, recognized as a virulent pathogen. It is responsible for a wide variety of infections, some of which being associated with biofilm production, such as implanted medical devices infections or endocarditis. However, little is known about S. lugdunensis virulence regulation. Two-component regulatory systems (TCS) play critical roles in bacterial adaptation, survival and virulence. Among them, LytSR is widely conserved, but has variable roles in different organisms, all being connected to metabolism or cell death and lysis into biofilms. Therefore, we investigated here the functions of LytSR in S. lugdunensis pathogenesis. Deletion of lytSR in S. lugdunensis DSM 4804 strain did not alter neither the susceptibility to Triton X-100 induced autolysis nor the death induced by antibiotics targeting cell wall synthesis. Interestingly, ΔlytSR biofilm was characterized by a lower biomass, a lack of tower structures and a higher rate of dead cells compared to the wild-type strain. Virulence towards Caenorhabditis elegans using slow-killing assay was significantly reduced for the mutant compared to the wild-type strain. In contrast, the deletion of lytSR had no effect on S. lugdunensis cytotoxicity towards the human keratinocyte cell line HaCaT. Transcriptional analyses conducted at mid- and late-exponential phases showed that lytSR deletion affected the expression of 286 genes. Most of them were involved in basic functions such as metabolism of amino acid, carbohydrates and nucleotides. Furthermore, LytSR appeared to be involved in the regulation of genes coding known or putative virulence and colonization factors, including the fibrinogen-binding protein Fbl, the major autolysin AtlL and the type VII secretion system. Overall, our data suggest that LytSR TCS is implicated in S. lugdunensis pathogenesis, through its involvement in biofilm formation and potentially by the control of genes encoding putative virulence factors.

ORGANISM(S): Staphylococcus lugdunensis

PROVIDER: GSE139909 | GEO | 2019/11/06

REPOSITORIES: GEO

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Project description:The mechanisms leading to the vancomycin-intermediate Staphylococcus aureus (VISA) phenotype are incompletely understood. In an effort to identify VISA determinants, clinical hVISA strain MM66 and its 1st-step VISA mutants were compared. S. aureus microarrays, array data analysis protocols (NIAID's Pathogen Functional Genomics Resource Center), as well as comparative genomic sequencing (CGS) were utilized to determine VISA transcriptome alterations and mutations that define the MM66 VISA mechanism. In addition, whole cell autolysis, antimicrobial susceptibility tests, growth in the presence of salt, coagulase and hemolysis assays were performed to confirm VISA transcriptional alterations. Overall, 2 MM66 VISA demonstrated 85 up-regulated and 8 down-regulated genes in common. SAMMD (Staphylococcus aureus Microarray Metadatabase) analysis identified a significant differential gene expression overlap between the global stress response regulator sigB-controlled genes in MM66-3 and MM66-4. CGS analysis on a MM66 VISA revealed two mutations in: a sensory box histidine kinase (yycG) and a putative adenine phosphoribosyltransferase (apt). The yycFG two-component system has been reported to regulate whole cell autolysis and MM66 VISA demonstrated reduced whole cell autolysis. Five ssaA homologues (putative amidases) and a gene that expresses a bifunctional autolysin (atlA) controlled by YycFG were downregulated in MM66 VISA. One MM66 VISA mutant demonstrated drastic downregulation of a gene cluster (betA, gbsA, betB, and cudT) required for the osmoprotective response of S. aureus and MM66 VISA mutants demonstrated reduced growth in high salt media compared to MM66. Virulence genes were also downregulated (coa, hla, hlb, hlgA, hlgB, and hlgC) in 2 MM66 VISA mutants which also demonstrated reduced coagulase and hemolytic activities compared to MM66. pur operon genes were also upregulated in MM66 VISA and it is interesting that we have also found an apt mutation, since Apt activity can be inhibited by high AMP levels and reduces the conversion of AMP into adenine. Conclusion: Mutations in yycG and apt allow hVISA to acquire the VISA phenotype and yycFG is involved with altered autolytic activity in MM66 VISA.

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Role of the LytSR two-component regulatory system in Staphylococcus lugdunensis biofilm formation and pathogenesis

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