Streptococcus mutans, an organism strongly associated with dental caries, utilizes a peptide-based cell density dependent signaling system known as quorum-sensing (QS). This signaling pathway is responsible for controlling major virulence traits such as bacteriocin production, biofilm formation, competence development, and stress tolerance. In S. mutans, one of the peptides responsible for cell-cell communication is competence- stimulating peptide (CSP). CSP acts as a signaling molecule to activate a two-component signal transduction pathway called ComDE. CSP is synthesized inside the cell as a pre-peptide of 46-residues long, in which the N-terminal 25-residue functions as a leader peptide. During secretion through a dedicated ABC transporter, the leader peptide is cleaved and the matured 21-residue long peptide (CSP21) is concentrated in the milieu. Our group was the first to identify the dedicated ABC transporter (NlmTE) necessary for CSP secretion. We also discovered that CSP21 is further processed by a highly conserved cell-surface associated protease, which we named SepM. We found that SepM cleaves CSP21 at the C-terminal end to create an 18-residue long active signaling molecule (CSP18). When extracellular concentration of CSP18 reaches a critical density, the ComD sensor kinase is activated by the peptide. The activated ComD then stimulates the ComE response regulator and a variety of genes necessary for the observed phenotypic changes are induced by the activated ComE. While the ComDE pathway is well studied at the phenotypic level, the molecular mechanisms by which CSP activates this signaling pathway have not been evaluated. In this application we propose to study the molecular mechanisms of CSP mediated cell-cell communication in S. mutans. Successful completion of this study could shed light on the molecular basis for inhibition of S. mutans biofilm formation through disruption of cell-cell communication.

Public Health Relevance

Streptococcus mutans, an oral bacterium associated with dental caries, forms dental plaque, which is a complex biofilm composed of hundreds of species. The major focus of this application is to understand a key cell-cell signaling pathway required for dental plaque development and oral colonization by S. mutans. Since the cell-cell signaling system under study is highly conserved, our study could shed light on the molecular basis for inhibition of S. mutans biofilm formation through disruption of cell-cell communication.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE026955-03
Application #
9750517
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lunsford, Dwayne
Project Start
2017-08-01
Project End
2021-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Kansas
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160