The overall goal of this project is to understand quorum sensing: the process of cell-cell communication in bacteria. The proposed research will probe the exquisite capacity of quorum-sensing receptors to differentiate between closely related, extracellular signal molecules and to exploit their structural differences to regulate signaling activity (Aim 1) The research will define the mechanisms by which the information encoded in the extracellular chemicals is relayed internally and interpreted by the vibrio Qrr small regulatory RNAs to precisely control the global gene expression program underpinning collective behaviors (Aim 2).
Aim 3 focuses on our recent discovery of a new quorum-sensing system consisting of a novel extracellular signal molecule, a new cytoplasmic receptor, a new regulatory small RNA, and its 17 target genes. The new extracellular quorum- sensing signal molecule is likely generated by the host microbiota and this is relevant during Vibrio cholerae infection. The proposed research is multidisciplinary, employing microbiology, genetics, biochemistry, structural biology, chemistry, physics theory, evolution, imaging, and engineering. At the most general level, the work will provide insight into intra- and inter-species communication, population-level cooperation, and the network principles underlying signal transduction and information processing. At a more specific level, the research will advance understanding of how quorum-sensing receptors accurately detect, distinguish between, and decode information contained in extracellular small molecules and how that information, once transduced into the cell, is conveyed to control gene expression, and ultimately behavior. At a practical level, my group's investigations could lead to strategies for controlling quorum sensing, potentially resulting in th development of anti- microbial drugs aimed at bacteria that use quorum sensing to control virulence and biofilm formation, and improved industrial production of high-value natural products. As in the previous project period, two vibrio species (Vibrio cholerae and Vibrio harveyi) are under study, providing insight into how closely related species have, through evolution, uniquely optimized their quorum-sensing circuits to perform distinct biology.

Public Health Relevance

Quorum sensing is a mechanism of cell-cell communication that allows bacteria to synchronously control processes that are only productive when undertaken in unison by the collective. This proposal focuses on defining the mechanisms that enable quorum-sensing receptors to accurately detect, distinguish between, and decode the information contained in extra-cellular small molecule signals and how that information, once it is transduced inside of the cell, is integrated and interpreted to control gene expression, and ultimately behavior. These investigations could lead to strategies for controlling quorum sensing, potentially resulting in th development of anti-microbial drugs aimed at bacteria that use quorum sensing to control virulence and biofilm formation, and improved industrial production of high-value natural products.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM065859-14
Application #
9221339
Study Section
Prokaryotic Cell and Molecular Biology Study Section (PCMB)
Program Officer
Reddy, Michael K
Project Start
2002-08-01
Project End
2020-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
14
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Princeton University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08543
Mukherjee, Sampriti; Moustafa, Dina A; Stergioula, Vasiliki et al. (2018) The PqsE and RhlR proteins are an autoinducer synthase-receptor pair that control virulence and biofilm development in Pseudomonas aeruginosa. Proc Natl Acad Sci U S A 115:E9411-E9418
Silpe, Justin E; Bassler, Bonnie L (2018) A Host-Produced Quorum-Sensing Autoinducer Controls a Phage Lysis-Lysogeny Decision. Cell :
Høyland-Kroghsbo, Nina Molin; Muñoz, Katrina Arcelia; Bassler, Bonnie L (2018) Temperature, by Controlling Growth Rate, Regulates CRISPR-Cas Activity in Pseudomonas aeruginosa. MBio 9:
Kim, Minyoung Kevin; Zhao, Aishan; Wang, Ashley et al. (2017) Surface-attached molecules control Staphylococcus aureus quorum sensing and biofilm development. Nat Microbiol 2:17080
Paczkowski, Jon E; Mukherjee, Sampriti; McCready, Amelia R et al. (2017) Flavonoids Suppress Pseudomonas aeruginosa Virulence through Allosteric Inhibition of Quorum-sensing Receptors. J Biol Chem 292:4064-4076
Papenfort, Kai; Silpe, Justin E; Schramma, Kelsey R et al. (2017) A Vibrio cholerae autoinducer-receptor pair that controls biofilm formation. Nat Chem Biol 13:551-557
Mukherjee, Sampriti; Moustafa, Dina; Smith, Chari D et al. (2017) The RhlR quorum-sensing receptor controls Pseudomonas aeruginosa pathogenesis and biofilm development independently of its canonical homoserine lactone autoinducer. PLoS Pathog 13:e1006504
Yan, Jing; Nadell, Carey D; Stone, Howard A et al. (2017) Extracellular-matrix-mediated osmotic pressure drives Vibrio cholerae biofilm expansion and cheater exclusion. Nat Commun 8:327
Yan, Jing; Nadell, Carey D; Bassler, Bonnie L (2017) Environmental fluctuation governs selection for plasticity in biofilm production. ISME J 11:1569-1577
Nadell, Carey D; Ricaurte, Deirdre; Yan, Jing et al. (2017) Flow environment and matrix structure interact to determine spatial competition in Pseudomonas aeruginosa biofilms. Elife 6:

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