The PI for this project, Dr. E. P. Greenberg has worked on quorum sensing for over 25 years. His long-term goals are to investigate the molecular mechanisms of social activity in bacteria, and to learn about why, when, where and how cooperative behavior exists. This proposal is to continue studies on quorum sensing in Pseudomonas aeruginosa. Prior work on this project has established that P. aeruginosa employs two quorum-sensing signals to govern expression of a battery of genes in a complex fashion. Although it is clear that P. aeruginosa shows substantial diversity as a species quorum sensing has been studied primarily in the context of the single strain PAO1, which was isolated from a human infection. In addition to the two known quorum-sensing signal and receptor circuits, Dr. Greenberg has shown there is a so-called orphan receptor for one of the signals, 3-oxo-C12-homoserine lactone. There are two receptors for this single signal. There are fundamental biological questions about the value of possessing two receptors for a single signal. In addition, the complete quorum-sensing systems are required for virulence of this opportunistic pathogen and the orphan receptor appears to suppress virulence. The proposed research derives from recent work on this project and represents a next logical set of about the biological significance of P. aeruginosa quorum sensing. We will study P. aeruginosa strains other than PAO1 to identify genes universally regulated by quorum sensing in this species and to gain insights about how environment might influence the makeup of the regulon. We will test two hypotheses that each address why P. aeruginosa might possess two receptors for the same signal. The relevance of this research to public health is that P. aeruginosa can cause difficult to resolve and often incurable human infections. Although it is unlikely that quorum sensing evolved to activate functions for human infections it is nevertheless true that quorum sensing is required for full P. aeruginosa virulence in a variety of animal infection models. Perhaps because of the quorum sensing involvement in virulence, cell-cell communication and cooperative behavior in P. aeruginosa are at the forefront of our knowledge of bacterial social behavior. The work proposed here will lend insight into the selective advantage of bacterial communication and cooperative behavior.

Public Health Relevance

This research program has developed a mechanistic understanding of quorum sensing in Pseudomonas aeruginosa, an opportunistic pathogen that causes devastating human infections. Because quorum sensing controls virulence of P. aeruginosa it has become a target for therapeutic development. The proposed research aims to increase our understanding of the elements of the P. aeruginosa quorum sensing system and how this bacterium uses quorum sensing to control its social activities. The findings will provide guidance about how to effectively target quorum sensing in the course of an infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059026-13
Application #
8063523
Study Section
Prokaryotic Cell and Molecular Biology Study Section (PCMB)
Program Officer
Singh, Shiva P
Project Start
1999-05-01
Project End
2012-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
13
Fiscal Year
2011
Total Cost
$322,828
Indirect Cost
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Ding, Fengming; Oinuma, Ken-Ichi; Smalley, Nicole E et al. (2018) The Pseudomonas aeruginosa Orphan Quorum Sensing Signal Receptor QscR Regulates Global Quorum Sensing Gene Expression by Activating a Single Linked Operon. MBio 9:
Brotherton, Carolyn A; Medema, Marnix H; Greenberg, E Peter (2018) luxR Homolog-Linked Biosynthetic Gene Clusters in Proteobacteria. mSystems 3:
Schaefer, Amy L; Harwood, Caroline S; Greenberg, E Peter (2018) ""Hot Stuff"": The Many Uses of a Radiolabel Assay in Detecting Acyl-Homoserine Lactone Quorum-Sensing Signals. Methods Mol Biol 1673:35-47
Liao, Lisheng; Schaefer, Amy L; Coutinho, Bruna G et al. (2018) An aryl-homoserine lactone quorum-sensing signal produced by a dimorphic prosthecate bacterium. Proc Natl Acad Sci U S A 115:7587-7592
Puri, Aaron W; Mevers, Emily; Ramadhar, Timothy R et al. (2018) Tundrenone: An Atypical Secondary Metabolite from Bacteria with Highly Restricted Primary Metabolism. J Am Chem Soc 140:2002-2006
Dong, Shi-Hui; Frane, Nicole D; Christensen, Quin H et al. (2017) Molecular basis for the substrate specificity of quorum signal synthases. Proc Natl Acad Sci U S A 114:9092-9097
Toussaint, Jean-Paul; Farrell-Sherman, Anna; Feldman, Tamar Perla et al. (2017) Gene Duplication in Pseudomonas aeruginosa Improves Growth on Adenosine. J Bacteriol 199:
Puri, Aaron W; Schaefer, Amy L; Fu, Yanfen et al. (2017) Quorum Sensing in a Methane-Oxidizing Bacterium. J Bacteriol 199:
Whiteley, Marvin; Diggle, Stephen P; Greenberg, E Peter (2017) Progress in and promise of bacterial quorum sensing research. Nature 551:313-320
Scholz, Rebecca L; Greenberg, E Peter (2017) Positive Autoregulation of an Acyl-Homoserine Lactone Quorum-Sensing Circuit Synchronizes the Population Response. MBio 8:

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