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The two-component response regulator LiaR regulates cell wall stress responses, pili expression and virulence in group B Streptococcus.

ABSTRACT: Group B Streptococcus (GBS) remains the leading cause of early onset sepsis among term infants. Evasion of innate immune defences is critical to neonatal GBS disease pathogenesis. Effectors of innate immunity, as well as numerous antibiotics, frequently target the peptidoglycan layer of the Gram-positive bacterial cell wall. The intramembrane-sensing histidine kinase (IM-HK) class of two-component regulatory systems has been identified as important to the Gram-positive response to cell wall stress. We have characterized the GBS homologue of LiaR, the response regulator component of the Lia system, to determine its role in GBS pathogenesis. LiaR is expressed as part of a three-gene operon (liaFSR) with a promoter located upstream of liaF. A LiaR deletion mutant is more susceptible to cell wall-active antibiotics (vancomycin and bacitracin) as well as antimicrobial peptides (polymixin B, colistin, and nisin) compared to isogenic wild-type GBS. LiaR mutant GBS are significantly attenuated in mouse models of both GBS sepsis and pneumonia. Transcriptional profiling with DNA microarray and Northern blot demonstrated that LiaR regulates expression of genes involved in microbial defence against host antimicrobial systems including genes functioning in cell wall synthesis, pili formation and cell membrane modification. We conclude that the LiaFSR system, the first member of the IM-HK regulatory systems to be studied in GBS, is involved in sensing perturbations in the integrity of the cell wall and activates a transcriptional response that is important to the pathogenesis of GBS infection.

SUBMITTER: Klinzing DC

PROVIDER: S-EPMC3749725 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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The two-component response regulator LiaR regulates cell wall stress responses, pili expression and virulence in group B Streptococcus.

Klinzing David C DC Ishmael Nadeeza N Hotopp Julie C Dunning JCD Tettelin Hervé H Shields Kelly R KR Madoff Lawrence C LC Puopolo Karen M KM

Microbiology (Reading, England) 20130523 Pt 7

Group B Streptococcus (GBS) remains the leading cause of early onset sepsis among term infants. Evasion of innate immune defences is critical to neonatal GBS disease pathogenesis. Effectors of innate immunity, as well as numerous antibiotics, frequently target the peptidoglycan layer of the Gram-positive bacterial cell wall. The intramembrane-sensing histidine kinase (IM-HK) class of two-component regulatory systems has been identified as important to the Gram-positive response to cell wall stre ...[more]

PMID: 23704792

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Project description:Group B Streptococcus (GBS; Streptococcus agalactiae) is a leading cause of sepsis in neonates and pregnant mothers worldwide. Whereas the hyper-virulent serogroup III clonal cluster 17 has been associated with neonatal disease and meningitis, serogroup III ST283 was recently implicated in invasive disease among non-pregnant adults in Asia. Here, through comparative genome analyses of invasive and non-invasive ST283 strains, we identified a truncated DNA-binding regulator of a two-component system in a non-invasive strain that was homologous to Bacillus subtilis bceR, encoding the bceRSAB response regulator, which was conserved among GBS strains. Using isogenic knockout and complementation mutants of the ST283 strain, we demonstrated that resistance to bacitracin and the human antimicrobial peptide cathelicidin LL-37 was reduced in the ΔbceR strain with MICs changing from 64 and 256 μg/ml to 0.25 and 64 μg/ml, respectively. Further, the ATP-binding cassette transporter was upregulated by sub-inhibitory concentrations of bacitracin in the wild-type strain. Upregulation of dltA in the wild-type strain was also observed and thought to explain the increased resistance to antimicrobial peptides. DltA, an enzyme involved in D-alanylation during the synthesis of wall teichoic acids, which mediates reduced antimicrobial susceptibility, was previously shown to be regulated by the bceR-type regulator in Staphylococcus aureus. In a murine infection model, we found that the ΔbceR mutation significantly reduced the mortality rate compared to that with the wild-type strain (p < 0.01). Moreover, this mutant was more susceptible to oxidative stress compared to the wild-type strain (p < 0.001) and was associated with reduced biofilm formation (p < 0.0001). Based on 2-DGE and mass spectrometry, we showed that downregulation of alkyl hydroperoxide reductase (AhpC), a Gls24 family stress protein, and alcohol dehydrogenase (Adh) in the ΔbceR strain might explain the attenuated virulence and compromised stress response. Together, we showed for the first time that the bceR regulator in GBS plays an important role in bacitracin and antimicrobial peptide resistance, virulence, survival under oxidative stress, and biofilm formation.

Dataset Information

The two-component response regulator LiaR regulates cell wall stress responses, pili expression and virulence in group B Streptococcus.

Publications

The two-component response regulator LiaR regulates cell wall stress responses, pili expression and virulence in group B Streptococcus.

Similar Datasets

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