Little is understood about the physiological or regulatory factors of Streptococcus pyogenes that enable switching between its commensal-like and virulent states. This proposal describes experimental approaches that seek to continue defining and characterizing quorum-sensing regulatory pathways that correspond to phenotypes consistent with the avirulent lifestyle of Streptococcus pyogenes (Group A Streptococcus; GAS). The quorum sensing network in Streptococcus pyogenes utilizing short hydrophobic peptide (SHP) pheromones and the pheromone receptors Rgg2 and Rgg3 regulates several phenotypes, including biofilm development, cell aggregation, aminoglycoside susceptibility, and lysozyme resistance, by an unknown mechanism. Our studies indicate that each of these phenotypes depend upon the expression of a small protein of unknown function. We hypothesize that this protein, referred to as StcB, is an inhibitor of an enzyme(s) that targets peptidoglycan bonds of the cell wall. Additional studies indicate the target of StcB is a murein hydrolase enzyme, called Isp, that contains cysteine and histidine-dependent amidohydrolase/peptidase (CHAP) and acetylglucosaminidase domains. Governance of StcB and Isp by the Rgg2/3 quorum sensing pathway accounts for significant changes to the bacterial cell surface, resulting in differential attachment to fibronectin and epithelial cells, and differential immuno- modulatory activities. This proposal seeks to elucidate the mechanisms by which StcB and Isp enzymes account for biochemical changes to the surface of S. pyogenes, how these changes lead to differential activity of surface structures and proteins, and how these changes affect the ability of S. pyogenes to colonize the host and modulate immune activities.

Public Health Relevance

Asymptomatic carriage of many bacterial pathogens in the human body serves as the reservoir for periodic outbreak of infectious disease, yet little is understood about the physiological and regulatory factors that sustain asymptomatic relationships, or about the signals accounting for the switch between commensal and virulent states. This proposal describes experimental approaches that will define and characterize recently discovered communication pathways and the physiological states under their regulation in Streptococcus pyogenes (Group A Streptococcus; GAS). Our studies are likely to provide mechanistic explanations for how these bacteria transition between harmless and harmful states. Our studies have identified small-molecule modulators of these communication pathways and thus may provide new leads in the development of alternative therapeutics to antibiotics as a way to treat infectious diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI091779-07
Application #
9384714
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
GU, Xin-Xing
Project Start
2011-07-01
Project End
2021-10-31
Budget Start
2017-11-01
Budget End
2018-10-31
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
098987217
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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