Quorum sensing is a bacterial communication process that relies on the production, detection, and group- wide response to extracellular signaling molecules called autoinducers. Quorum sensing enables groups of bacteria to synchronously alter behavior in response to changes in population density and species composition of the vicinal community.
In Aim 1, an investigation of phage-bacteria-eukaryote quorum-sensing-mediated interactions will be undertaken. The proposed research seeks to explore newly-discovered inter-kingdom quorum- sensing-mediated communication pathways that shape host-microbe-phage interactions. Mutagenesis, bioassays, small molecule purification, and crystallography will be used to define the mechanisms by which phages, in response to host quorum-sensing information, launch their lytic programs. The native cue that is released from lysed bacterial cells that appears to be the key input that activates the phage quorum-sensing eavesdropping program will be purified. More complex mechanisms that underlie phage infections of the human microbiome, how affected bacteria avoid phage infection, how phage infection of microbiome bacteria affects health-promoting and harmful gut microbes will be investigated. The team will use what is learned to guide the development of phage therapies to combat human diseases.
In Aim 2, the team will image the bacterial biofilm dispersal process and discover the key components. Quorum sensing controls the development of surface-associated communities called biofilms, a predominant form of bacterial life on Earth. Biofilms are notorious for causing infections and damage to surfaces. Unlike biofilm formation, almost nothing is known about the second half of the biofilm lifestyle, biofilm dispersal. The team will develop a new imaging system with light sheet fluorescence microscopy (LSFM) that will enable imaging of the biofilm dispersal process. By imaging, at single-cell resolution, bacteria exiting biofilms the team will discover when dispersal occurs, if cells leave individually or collectively, and whether or not the process is globally synchronized. Using fluorescent reporters to quorum-sensing- controlled genes, quorum-sensing activity during dispersal will be monitored. The unique and combined contributions of the different autoinducers in driving/suppressing biofilm dispersal will be studied.
This aim will provide leads for manipulating dispersal, a key step in bacterial lifecycles incl uding those of global pathoqens.

Public Health Relevance

Bacterial pathogens require quorum sensing for infection. An important practical aspect of these investigations is the development of anti-quorum-sensing therapies including new phage therapies as alternatives to traditional antibiotics.

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 #
4R37GM065859-18
Application #
9962533
Study Section
Special Emphasis Panel (NSS)
Program Officer
Coyne, Robert Stephen
Project Start
2020-12-01
Project End
2025-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
18
Fiscal Year
2021
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
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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:
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
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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:
Høyland-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
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
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

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