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 #
5R01GM059026-12
Application #
7793557
Study Section
Prokaryotic Cell and Molecular Biology Study Section (PCMB)
Program Officer
Anderson, James J
Project Start
1999-05-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
12
Fiscal Year
2010
Total Cost
$326,371
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
Scholz, Rebecca L; Greenberg, E Peter (2017) Positive Autoregulation of an Acyl-Homoserine Lactone Quorum-Sensing Circuit Synchronizes the Population Response. MBio 8:
Toussaint, Jean-Paul; Farrell-Sherman, Anna; Feldman, Tamar Perla et al. (2017) Gene Duplication in Pseudomonas aeruginosa Improves Growth on Adenosine. J Bacteriol 199:
Tseng, Boo Shan; Majerczyk, Charlotte D; Passos da Silva, Daniel et al. (2016) Quorum Sensing Influences Burkholderia thailandensis Biofilm Development and Matrix Production. J Bacteriol 198:2643-50
Feltner, John B; Wolter, Daniel J; Pope, Christopher E et al. (2016) LasR Variant Cystic Fibrosis Isolates Reveal an Adaptable Quorum-Sensing Hierarchy in Pseudomonas aeruginosa. MBio 7:
Majerczyk, Charlotte; Schneider, Emily; Greenberg, E Peter (2016) Quorum sensing control of Type VI secretion factors restricts the proliferation of quorum-sensing mutants. Elife 5:
Truong, Thao T; Seyedsayamdost, Mohammad; Greenberg, E Peter et al. (2015) A Burkholderia thailandensis Acyl-Homoserine Lactone-Independent Orphan LuxR Homolog That Activates Production of the Cytotoxin Malleilactone. J Bacteriol 197:3456-62
Scholz, Rebecca L; Greenberg, E Peter (2015) Sociality in Escherichia coli: Enterochelin Is a Private Good at Low Cell Density and Can Be Shared at High Cell Density. J Bacteriol 197:2122-8
Amunts, Alexey; Fiedorczuk, Karol; Truong, Thao T et al. (2015) Bactobolin A binds to a site on the 70S ribosome distinct from previously seen antibiotics. J Mol Biol 427:753-5
Wang, Meizhen; Schaefer, Amy L; Dandekar, Ajai A et al. (2015) Quorum sensing and policing of Pseudomonas aeruginosa social cheaters. Proc Natl Acad Sci U S A 112:2187-91
Majerczyk, Charlotte D; Brittnacher, Mitchell J; Jacobs, Michael A et al. (2014) Cross-species comparison of the Burkholderia pseudomallei, Burkholderia thailandensis, and Burkholderia mallei quorum-sensing regulons. J Bacteriol 196:3862-71

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