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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI091779-04
Application #
8683085
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
GU, Xin-Xing
Project Start
2011-07-01
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60612
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
Shanker, Erin; Morrison, Donald A; Talagas, Antoine et al. (2016) Pheromone Recognition and Selectivity by ComR Proteins among Streptococcus Species. PLoS Pathog 12:e1005979
Chang, Jennifer C; Federle, Michael J (2016) PptAB Exports Rgg Quorum-Sensing Peptides in Streptococcus. PLoS One 11:e0168461
Wilkening, Reid V; Chang, Jennifer C; Federle, Michael J (2016) PepO, a CovRS-controlled endopeptidase, disrupts Streptococcus pyogenes quorum sensing. Mol Microbiol 99:71-87
Talagas, Antoine; Fontaine, Laetitia; Ledesma-García, Laura et al. (2016) Structural Insights into Streptococcal Competence Regulation by the Cell-to-Cell Communication System ComRS. PLoS Pathog 12:e1005980
Jassim, Sarmad H; Sivaraman, Kavitha R; Jimenez, Juan Cristobal et al. (2015) Bacteria Colonizing the Ocular Surface in Eyes With Boston Type 1 Keratoprosthesis: Analysis of Biofilm-Forming Capability and Vancomycin Tolerance. Invest Ophthalmol Vis Sci 56:4689-96
Chang, Jennifer C; Jimenez, Juan Cristobal; Federle, Michael J (2015) Induction of a quorum sensing pathway by environmental signals enhances group A streptococcal resistance to lysozyme. Mol Microbiol 97:1097-113

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