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, and the selective pressures favoring quorum sensing control of gene expression and the costs and benefits of quorum sensing in P. aeruginosa. It is thought that quorum sensing functions to control and coordinate cooperative behaviors, a generally accepted view that is supported by limited experimental evidence. 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 begin to address the costs and benefits of controlling cooperative behavior by quorum sensing. Specifically, we aim to understand why growth on transported solutes is (infrequently) linked to quorum sensing. We will investigate molecular policing mechanisms that can punish quorum-sensing signal receptor mutants (mutants that do not produce any quorum-regulated public or shared resources). We will uncouple activation of the quorum regulon, or specific quorum-controlled factors from acyl-HSL signaling, and use our uncoupled mutants in binary culture experiments with parent strains to measure the costs and benefits of controlling the regulon or elastase by quorum sensing. The proposed experiments will provide us with experimental data critical for understanding the relationship between intercellular communication and cooperativity. We will examine the quorum-regulated transcriptomes and metabolomes of P. aeruginosa isolates from different environments. Our hypothesis is that the regulons will reflect the ecology of the isolate.

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. Quorum sensing research also affords us a window into the social behavior of bacteria at a molecular level.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059026-16
Application #
8628667
Study Section
Special Emphasis Panel (ZRG1-GGG-T (02))
Program Officer
Sledjeski, Darren D
Project Start
1999-05-01
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
16
Fiscal Year
2014
Total Cost
$341,844
Indirect Cost
$120,586
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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