Streptococcus mutants, the primary etiological agent of dental caries, utilizes a peptide-based quorum-sensing (QS) pathway to control major virulence attributes including competence development, acid stress tolerance, bacteriocin production, and biofilm formation. In S. mutans, the peptide involved in QS is called competence-stimulating peptide (CSP), which activates a ComDE two-component signal transduction pathway. This peptide is synthesized inside the cell as a 46-residue pre-peptide with a 25-residue long leader sequence. During secretion through a dedicated ABC transporter, the leader peptide is removed, and the matured peptide, which is 21-residues long (CSP21), is accumulated in the milieu. We were the first to identify the ABC transporter, NlmTE, which is necessary for CSP secretion. We also found that CSP21 is further processed by a highly conserved cell-surface associated peptidase, SepM, which cleaves CSP21 at the C-terminal end to generate the active signaling molecule CSP18. When CSP18 reaches a critical density, it is then sensed by the ComD sensor kinase. The activated ComD then induces the ComE response regulator, which then activates a variety of genes necessary for the observed phenotypic changes. Although the phenotypic aspect of the ComDE pathway is well studied, the molecular mechanisms for CSP mediated activation is poorly studied. In this application, with the help of three Aims, we will attempt to understand the molecular details of CSP mediated QS in S. mutans. Successful completion of this study could provide the molecular basis for inhibition of streptococcal pathogenesis through disruption of cell-cell communication.
The major focus of this application is to understand quorum sensing in Streptococcus mutans, a human pathogen. Quorum sensing is an important biological process that controls biofilm formation, competence development, and virulence gene regulation. In this application, we want to identify the key signal processing systems that are required for quorum sensing in S. mutans and perhaps in other streptococci.
