title: Niche-specific contribution to streptococcal virulence of a MalR-regulated carbohydrate binding protein.
abstract: Low G+C Gram-positive bacteria typically contain multiple LacI/GalR regulator family members, which often have highly similar amino-terminal DNA binding domains, suggesting significant overlap in target DNA sequences. The LacI/GalR family regulator catabolite control protein A (CcpA) is a global regulator of the Group A Streptococcus (GAS) transcriptome and contributes to GAS virulence in diverse infection sites. Herein, we studied the role of the maltose repressor (MalR), another LacI/GalR family member, in GAS global gene expression and virulence. MalR inactivation reduced GAS colonization of the mouse oropharynx but did not detrimentally affect invasive infection. The MalR transcriptome was limited to only 25 genes, and a highly conserved MalR DNA-binding sequence was identified. Variation of the MalR binding sequence significantly reduced MalR binding in vitro. In contrast, CcpA bound to the same DNA sequences as MalR but tolerated variation in the promoter sequences with minimal change in binding affinity. Inactivation of pulA, a MalR regulated gene which encodes a cell surface carbohydrate binding protein, significantly reduced GAS human epithelial cell adhesion and mouse oropharyngeal colonization but did not affect GAS invasive disease. These data delineate a molecular mechanism by which hierarchical regulation of carbon source utilization influences bacterial pathogenesis in a site-specific fashion.
authors.affiliation: Department of Infectious Diseases, MD Anderson Cancer Center, Houston, TX 77030, USA. sshelburne@mdanderson.org
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Shelburne
authors.forename: Pranoti
authors.initials: P
authors.lastname: Sahasrobhajane
authors.forename: Bryce
authors.initials: B
authors.lastname: Suber
authors.forename: David B
authors.initials: DB
authors.lastname: Keith
authors.forename: Michael T
authors.initials: MT
authors.lastname: Davenport
authors.forename: Nicola
authors.initials: N
authors.lastname: Horstmann
authors.forename: Muthiah
authors.initials: M
authors.lastname: Kumaraswami
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Olsen
authors.forename: Richard G
authors.initials: RG
authors.lastname: Brennan
authors.forename: James M
authors.initials: JM
authors.lastname: Musser
mesh_terms: D000818:Animals; D001422:Bacterial Adhesion; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D002460:Cell Line; D017124:Conserved Sequence; D004269:DNA, Bacterial / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000382:microbiology; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial; D055786:Gene Knockout Techniques; D006801:Humans; D051379:Mice; D009960:Oropharynx / Q000382:microbiology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013297:Streptococcus pyogenes / Q000378:metabolism* / Q000472:pathogenicity*; D014774:Virulence; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D004269:DNA, Bacterial; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D037521:Virulence Factors; C084528:malR protein, bacteria; C055213:saccharide-binding proteins