title: An amino-terminal signal peptide of Vfr protein negatively influences RopB-dependent SpeB expression and attenuates virulence in Streptococcus pyogenes.
abstract: Streptococcal pyrogenic exotoxin B (SpeB) is an extracellular cysteine protease that is a critical virulence factor made by the major human pathogen group A Streptococcus (GAS). speB expression is dependent on the regulator of proteinase B (RopB) and is upregulated with increasing cell density and during infection. Because computer modelling suggested significant structural similarity between RopB and peptide-sensing regulatory proteins made by other Gram-positive bacteria, we hypothesized that speB expression is influenced by RopB-peptide interactions. Inactivation of the gene (vfr) encoding the virulence factor related (Vfr) protein resulted in increased speB transcript level during the exponential growth phase, whereas provision of only the amino-terminal region of Vfr comprising the secretion signal sequence in trans restored a wild-type speB expression profile. Addition of the culture supernatant from a Vfr signal peptide-expressing GAS strain restored wild-type speB transcript level to a vfr-inactivated isogenic mutant strain. A distinct peptide in the Vfr secretion signal sequence specifically bound to recombinant RopB. Finally, overexpression of the Vfr secretion signal sequence significantly decreased speB transcript level and attenuated GAS virulence in two mouse models of invasive infection. Taken together, these data delineate a previously unknown small peptide-mediated regulatory system that controls GAS virulence factor production.
authors: Department of Infectious Diseases, MD Anderson Cancer Center, Houston, TX, USA.
authors: Samuel A
authors: SA
authors: Shelburne
authors: Randall J
authors: RJ
authors: Olsen
authors: Nishanth
authors: N
authors: Makthal
authors: Nicholas G
authors: NG
authors: Brown
authors: Pranoti
authors: P
authors: Sahasrabhojane
authors: Ebru M
authors: EM
authors: Watkins
authors: Timothy
authors: T
authors: Palzkill
authors: James M
authors: JM
authors: Musser
authors: Muthiah
authors: M
authors: Kumaraswami
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005098:Exotoxins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D021382:Protein Sorting Signals; D016415:Sequence Alignment; D013290:Streptococcal Infections / Q000382:microbiology*; D013297:Streptococcus pyogenes / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D014774:Virulence; D037521:Virulence Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D005098:Exotoxins; D021382:Protein Sorting Signals; C098249:RopB protein, Rhizobium leguminosarum; D037521:Virulence Factors; C027951:erythrogenic toxin