title: 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.
authors.affiliation: Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA.|Channing Laboratory, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Klinzing
authors.affiliation: Institute for Genome Sciences, University of Maryland Baltimore, 801 West Baltimore Street, Baltimore, MD 21201, USA.|The J. Craig Venter Institute, 9712 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Nadeeza
authors.initials: N
authors.lastname: Ishmael
authors.affiliation: Institute for Genome Sciences, University of Maryland Baltimore, 801 West Baltimore Street, Baltimore, MD 21201, USA.|The J. Craig Venter Institute, 9712 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Julie C Dunning
authors.initials: JCD
authors.lastname: Hotopp
authors.affiliation: Institute for Genome Sciences, University of Maryland Baltimore, 801 West Baltimore Street, Baltimore, MD 21201, USA.|The J. Craig Venter Institute, 9712 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Hervé
authors.initials: H
authors.lastname: Tettelin
authors.affiliation: Channing Laboratory, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Shields
authors.affiliation: Massachusetts Department of Public Health, Jamaica Plain, MA 02130, USA.|Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, 55 Lake Avenue, North Worcester, MA 01655, USA.
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Madoff
authors.affiliation: Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA.|Department of Newborn Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.|Channing Laboratory, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Puopolo
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002473:Cell Wall / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D010861:Fimbriae, Bacterial / Q000235:genetics / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D018869:Heat-Shock Response; D006801:Humans; D007231:Infant, Newborn; D051379:Mice; D008969:Molecular Sequence Data; D018410:Pneumonia, Bacterial / Q000382:microbiology; D018805:Sepsis / Q000382:microbiology; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D013290:Streptococcal Infections / Q000382:microbiology; D013292:Streptococcus agalactiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D014774:Virulence
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins