An amino-terminal signal peptide of Vfr protein negatively influences RopB-dependent SpeB expression and attenuates virulence in Streptococcus pyogenes

Samuel Shelburne, Randall J. Olsen, Nishanth Makthal, Nicholas G. Brown, Pranoti Sahasrabhojane, Ebru M. Watkins, Timothy Palzkill, James M. Musser, Muthiah Kumaraswami

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Summary: 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.

Original languageEnglish (US)
Pages (from-to)1481-1495
Number of pages15
JournalMolecular Microbiology
Volume82
Issue number6
DOIs
StatePublished - Dec 2011

ASJC Scopus subject areas

  • Microbiology
  • Molecular Biology

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