Group A Streptococcus (GAS), a pathogen capable of both localized and systemic infection, is known to secrete numerous virulence factors in temporal patterns during growth in vitro and in vivo, indicating the presence of intricate regulatory circuits. An inverse relationship exists between expression levels of the secreted cysteine protease, SpeB, and severity of disease [1-3]. The so-called """"""""stand-alone"""""""" regulator Rgg (also known as RopB) is required, but is not sufficient, for expression of SpeB. An unknown growth-phase-dependent factor is additionally required, but has remained elusive [4-6]. Our preliminary data demonstrate that the unknown factor is a bacterially-produced pheromone with properties consistent with a small peptide. Additionally, analysis predicts that Rgg is a peptide-binding transcription factor with structural homology to PlcR and PrgX of other quorum sensing systems. The overall hypothesis to be tested is that a pheromone modulates the activity of Rgg for the purpose of controlling speB transcription. This is a departure from the paradigm that the Rgg-dependent pathway responds to environmental changes;instead, we provide compelling evidence that GAS produces its own impetus to induce speB. Our preliminary results demonstrate that Rgg paralogs found in GAS are indeed responsive to small peptide pheromones, providing a convincing precedent for our hypothesis and are the first examples that Rgg proteins are quorum sensing effectors. The goal of our research will be to define the signaling pheromone(s) present in culture supernatants and characterize the mechanism for its production and recognition by GAS. Genetic disruption of these systems will be tested for their contributions in localized and invasive infection models. Demonstration that GAS utilizes Rgg proteins for cell-to-cell signaling will provide a foundation for future development of therapies designed to interfere with intercellular signaling in GAS and in other Rgg-containing organisms.
We are defining how Group A Streptococcus uses cell-to-cell communication to regulate expression of genes contributing to its virulence. We have found that a previously uncharacterized pheromone controls expression of a major virulence factor. We will conduct experiments designed to elucidate what this pheromone is, how it is made, and how it elicits its control of gene expression. Our research will provide a basis for alternative antimicrobial therapies aimed at interfering with bacterial communication to control virulence.
|Pérez Morales, Tiara G; Ratia, Kiira; Wang, Duo-Sheng et al. (2018) A novel chemical inducer of Streptococcus quorum sensing acts by inhibiting the pheromone-degrading endopeptidase PepO. J Biol Chem 293:931-940|
|Cook, Laura C C; Hu, Hong; Maienschein-Cline, Mark et al. (2018) A Vaginal Tract Signal Detected by the Group B Streptococcus SaeRS System Elicits Transcriptomic Changes and Enhances Murine Colonization. Infect Immun 86:|
|Mashburn-Warren, Lauren; Goodman, Steven D; Federle, Michael J et al. (2018) The conserved mosaic prophage protein paratox inhibits the natural competence regulator ComR in Streptococcus. Sci Rep 8:16535|
|Pavlova, Sylvia I; Wilkening, Reid V; Federle, Michael J et al. (2018) Streptococcus endopeptidases promote HPV infection in vitro. Microbiologyopen :e00628|
|Gogos, Artemis; Jimenez, Juan Cristobal; Chang, Jennifer C et al. (2018) A Quorum Sensing-Regulated Protein Binds Cell Wall Components and Enhances Lysozyme Resistance in Streptococcus pyogenes. J Bacteriol 200:|
|Neiditch, Matthew B; Capodagli, Glenn C; Prehna, Gerd et al. (2017) Genetic and Structural Analyses of RRNPP Intercellular Peptide Signaling of Gram-Positive Bacteria. Annu Rev Genet 51:311-333|
|Talagas, Antoine; Fontaine, Laetitia; Ledesma-García, Laura et al. (2017) Correction: Structural Insights into Streptococcal Competence Regulation by the Cell-to-Cell Communication System ComRS. PLoS Pathog 13:e1006208|
|Shanker, Erin; Federle, Michael J (2017) Quorum Sensing Regulation of Competence and Bacteriocins in Streptococcus pneumoniae and mutans. Genes (Basel) 8:|
|Wilkening, Reid V; Capodagli, Glenn C; Khataokar, Atul et al. (2017) Activating mutations in quorum-sensing regulator Rgg2 and its conformational flexibility in the absence of an intermolecular disulfide bond. J Biol Chem 292:20544-20557|
|Wilkening, Reid V; Federle, Michael J (2017) Evolutionary Constraints Shaping Streptococcus pyogenes-Host Interactions. Trends Microbiol 25:562-572|
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