The overall goal of my research is to understand quorum sensing: the process of cell-cell communication in bacteria. Until recently, the ability of bacteria to communicate was considered an anomaly that occurred only in a few marine vibrio species. It is now clear that cell-cell communication is the norm in the bacterial world and that understanding this process is fundamental to all of microbiology, including industrial and clinical microbiology, and ultimately to understanding collective behaviors and development in higher organisms. We showed that Vibrio cholerae, a major pathogen in under-developed countries, has a quorum-sensing system and that this system controls virulence. We discovered that multiple quorum-sensing signals are channeled into one signaling circuit; yet the circuit enables differential gene expression in response to the different signal inputs. We also recently discovered that four redundant small regulatory RNAs (sRNAs) lie at the heart of the V. cholerae circuit, and that they mediate the quorum-sensing switch allowing V. cholerae cells to transition from acting as individuals to functioning as a coordinated group. Thus, the V. cholerae quorum- sensing circuit has revealed itself to be ideally suited for explorations of questions concerning how sensory information is integrated at the molecular level and how regulatory proteins controlled by multiple cues can nonetheless provide a mechanism for differential responses to those inputs. We will study V. cholerae to learn the mechanism by which sRNAs regulate behavior, and to discover the unique control features provided by sRNA regulators (as opposed to DNA-binding proteins). Finally, we will use V. cholerae to examine the molecular switch underlying quorum sensing, how individual behaviors give rise to collective behaviors, and to identify the genes that are critical for survival as an individual and as a member of a coordinated community. The above questions are the focus of this research application. At the most general level, these studies will provide insight into intra- and inter-species communication, population-level cooperation, and the network principles underlying signal transduction and information processing at the cellular level. At a more specific level, these studies will advance our understanding of the mechanisms of sRNA-mediated control of gene expression, the global nature of which has been, until recently, under- appreciated and under-studied in bacteria. Finally, at a practical level, these investigations could lead to synthetic strategies for controlling quorum sensing. Objectives include development of anti-microbial drugs aimed at bacteria that use quorum sensing to control virulence, and improved industrial production of natural products such as antibiotics. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM065859-06
Application #
7486222
Study Section
Prokaryotic Cell and Molecular Biology Study Section (PCMB)
Program Officer
Zatz, Marion M
Project Start
2002-08-01
Project End
2011-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
6
Fiscal Year
2008
Total Cost
$299,055
Indirect Cost
Name
Princeton University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
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
H√łyland-Kroghsbo, Nina M; Paczkowski, Jon; Mukherjee, Sampriti et al. (2017) Quorum sensing controls the Pseudomonas aeruginosa CRISPR-Cas adaptive immune system. Proc Natl Acad Sci U S A 114:131-135
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:
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; Bassler, Bonnie L (2017) Environmental fluctuation governs selection for plasticity in biofilm production. ISME J 11:1569-1577
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
Hurley, Amanda; Bassler, Bonnie L (2017) Asymmetric regulation of quorum-sensing receptors drives autoinducer-specific gene expression programs in Vibrio cholerae. PLoS Genet 13:e1006826
Yan, Jing; Sharo, Andrew G; Stone, Howard A et al. (2016) Vibrio cholerae biofilm growth program and architecture revealed by single-cell live imaging. Proc Natl Acad Sci U S A 113:E5337-43

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