Quorum sensing is a form of cell-cell communication that allows members of a population to coordinate activities in a cell density-dependent fashion. Quorum sensing has been shown to play a significant role in the virulence of Pseudomonas aeruginosa and other pathogens. This research program is focused on P. aeruginosa, which controls a battery of virulence factors by acyl-homoserine lactone quorum sensing. We have been, and will continue to be, interested in basic mechanisms of quorum sensing, the selective pressures favoring quorum-sensing control of gene expression, and the costs and benefits of quorum sensing in P. aeruginosa. Quorum sensing functions to control and coordinate cooperative behaviors. It is clear that cooperativity is an evolved biological phenomenon, but there is considerable controversy about the selective forces leading to cooperativity, what are the costs and benefits of cooperativity, and what are the possible advantages to controlling cooperativity by quorum sensing. We will use molecular genetic approaches to address the costs and benefits of controlling cooperative behavior by quorum sensing. Specifically, we aim to study constructed and evolved P. aeruginosa PA01 quorum-sensing mutants and recombinant E. coli to probe the costs and benefits of quorum sensing components and the networks of P. aeruginosa quorum sensing gene control circuits. We will also study naturally occurring quorum sensing mutants from cystic fibrosis patients and use these isolates to understand quorum sensing wiring options and the evolution of quorum sensing signal specificity in P. aeruginosa. By understanding quorum sensing in laboratory experiments and coupling this information to the quorum-sensing circuitry in clinical isolates we can understand how to manipulate quorum sensing and make inferences about conditions prevalent in P. aeruginosa infections. Such information is critical in attempts to develop quorum-sensing technologies for disease control.

Public Health Relevance

Pseudomonas aeruginosa is an opportunistic human pathogen that causes a variety of difficult or impossible to resolve infections. Because quorum sensing controls virulence in P. aeruginosa it has become a target for development of novel antimicrobials. Efforts to develop quorum-sensing inhibitors as therapeutics will rely on a better understanding of the role of quorum sensing in virulence and on a basic understanding of the selective pressures leading to quorum sensing control of gene expression in P. aeruginosa.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059026-20
Application #
9458200
Study Section
Prokaryotic Cell and Molecular Biology Study Section (PCMB)
Program Officer
Sledjeski, Darren D
Project Start
1999-05-01
Project End
2020-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
20
Fiscal Year
2018
Total Cost
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
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:
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:

Showing the most recent 10 out of 57 publications