Lewis-Thomas Lab, 305
Phone: (609) 258-5659
Fax: (609) 258-2957
Our lab wants to understand quorum sensing: the process of cell-cell communication in bacteria. Quorum sensing involves the production, release, and subsequent detection of chemical signal molecules called autoinducers. This process enables populations of bacteria to synchronously regulate gene expression, and therefore behavior, on a community-wide scale. Quorum sensing is widespread in the bacterial world, so understanding this process is fundamental to all of microbiology, including industrial and clinical microbiology, and ultimately to understanding the development of higher organisms. Our studies of quorum sensing are providing insight into intra- and inter-species communication, population-level cooperation, and the design principles underlying signal transduction and information processing at the cellular level. These investigations are also leading to synthetic strategies for controlling quorum sensing. Our 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.
We are pursuing our goal of understanding bacterial communication by combining genetics, biochemistry, structural biology, chemistry, microarray studies, bioinformatics, modeling, and engineering approaches.
The basic steps involved in detecting and responding to fluctuations in cell number are analogous in all known quorum-sensing systems. First, low molecular weight molecules called autoinducers are synthesized intracellularly. Second, these molecules are either passively released or actively secreted outside of the cells. As the number of cells in a population increases, the extracellular concentration of autoinducer likewise increases. Third, when autoinducers accumulate above the minimal threshold level required for detection, cognate receptors bind the autoinducers and trigger signal transduction cascades that result in population-wide changes in gene expression. Thus, quorum sensing enables cells in a population to function in unison and, in so doing, they carry out behaviors as a collective.
We focus on marine vibrios as model systems for quorum sensing because the first observation indicating that bacteria could communicate with multiple quorum-sensing autoinducers came with our definition of the quorum-sensing system of Vibrio harveyi. The V. harveyi quorum-quorum sensing system consists of three autoinducers and three cognate receptors functioning in parallel to channel information into a shared regulatory pathway (see Figure). We showed that beyond controlling gene expression on a global scale, quorum sensing allows bacteria to communicate within and between species. We demonstrated that HAI-1 is only produced by V. harveyi so it is used for intra-species communication. We discovered CAI-1 and showed that it is made by all vibrios and thus is used for intra-genera communication. By contrast, AI-2 is made and detected by a vast array of bacterial species. Thus, AI-2 is used for inter-species communication (see Figure).
By studying the signal transduction pathway that mediates responses to autoinducers, we discovered a set of redundant small RNAs (sRNAs), which we named the Qrr sRNAs that lie at the core of vibrio quorum-sensing cascades. Gene dosage compensation, coupled with a set of feedback loops, adjusts the total Qrr sRNA pool such that small perturbations in Qrr levels have profound effects on the output of the system. These sRNA changes track with changes in extracellular autoinducer levels. Precisely maintained Qrr levels are required to direct the proper timing and correct patterns of expression of quorum-sensing-regulated target genes. In the quorum-sensing regulon, the genes that are controlled by the Qrr sRNAs are the most rapid to respond to quorum-sensing autoinducers and presumably encode components required to instigate subsequent phases of the quorum-sensing program.
A more applied side of our research is focused on developing pro- and anti-quorum sensing molecules to be used as new therapeutics. Toward this end, we work on the human pathogen Vibrio cholerae, the causative agent of the endemic diarrheal disease cholera, and Pseudomonas aeruginosa, a pathogen that is devastating in cystic fibrosis patients, hospital burn units, and on sub-epithelial inserted medical devices such as intubation tubes, stents, and other long-term submerged prosthetics. In the case of V. cholerae, we showed that it possesses a quorum-sensing network similar to that of V. harveyi except the circuit controls virulence and biofilm formation.
Quorum sensing controls virulence in many bacterial pathogens and, typically, activation of virulence factor expression occurs at high cell density. Surprisingly, quorum sensing promotes V. cholerae virulence factor expression and biofilm formation at low cell density and represses these traits at high cell density. This opposite pattern of regulation in the case of V. cholerae can be understood in terms of the specific disease the bacterium causes. Following a successful V. cholerae infection, the ensuing diarrhea washes huge numbers of bacteria from the human intestine into the environment. Repression of virulence factor production and biofilm formation genes at high cell density promotes dissemination of V. cholerae. Thus, pro-quorum-sensing molecules, which signal the high cell density state, repress production of virulence factors.
Our findings suggest that manipulating quorum sensing could be used as a therapy to prevent cholera infection and, furthermore, that strategies to manipulate bacterial quorum sensing hold promise in the clinical arena. In the case of P. aeruginosa, quorum-sensing-directed virulence factor production and biofilm formation appear to be critical for infection. We developed molecules that inhibit P. aeruginosa quorum sensing and these molecules are effective at saving animals and human tissue culture cells from killing by this pathogen. The anti-Pseudomonas quorum-sensing molecules also prevent biofilm formation and clogging in microfluidics models of natural conditions for Pseudomonas such as soil, water filtration devices, and stents. Together the V. cholerae and P. aeruginosa work validates our notion that targeting quorum sensing has potential for antimicrobial drug development.
MacArthur Foundation Fellow (2002)
American Society for Microbiology, Eli Lilly and Company Research Award (2006)
Elected to The National Academy of Sciences (2006)
Elected to The American Academy of Arts and Sciences (2007)
Wiley Prize for Biomedical Science (2009)
The National Academy of Sciences Richard Lounsbery Award (2011)
L’Oreal-UNESCO Women in Science Award (2012)
Elected Foreign Member of the Royal Society (2012)
Elected to the American Philosophical Society (2012)
Elected Foreign Member of EMBO (2013)
Drescher, K.; Nadell, C. D.; Stone, H. A.; Wingreen, N. S.; Bassler, B. L., "Solutions to the Public Goods Dilemma in Bacterial Biofilms." Current Biology 2014, 24 (1), 50-55.
Ke, X.; Miller, L. C.; Ng, W.-L.; Bassler, B. L., "CqsA-CqsS quorum-sensing signal-receptor specificity in Photobacterium angustum." Molecular Microbiology 2014, 91 (4), 821-833.
Shao, Y.; Bassler, B. L., "Quorum regulatory small RNAs repress type VI secretion in Vibrio cholerae." Molecular Microbiology 2014, 92 (5), 921-930.
Perez, L. J.; Karagounis, T. K.; Hurley, A.; Bassler, B. L.; Semmelhack, M. F., "Highly potent, chemically stable quorum sensing agonists for vibrio Cholerae." Chemical Science 2014, 5 (1), 151-155.
van Kessel, J. C.; Rutherford, S. T.; Shao, Y.; Utria, A. F.; Bassler, B. L., "Individual and Combined Roles of the Master Regulators AphA and LuxR in Control of the Vibrio harveyi Quorum-Sensing Regulon." Journal of Bacteriology 2013, 195 (3), 436-443.
van Kessel, J. C.; Ulrich, L. E.; Zhulin, I. B.; Bassler, B. L., "Analysis of Activator and Repressor Functions Reveals the Requirements for Transcriptional Control by LuxR, the Master Regulator of Quorum Sensing in Vibrio harveyi." Mbio 2013, 4 (4).
Nadell, C. D.; Bucci, V.; Drescher, K.; Levin, S. A.; Bassler, B. L.; Xavier, J. B., "Cutting through the complexity of cell collectives." Proceedings of the Royal Society B-Biological Sciences 2013, 280 (1755).
Shao, Y.; Feng, L.; Rutherford, S. T.; Papenfort, K.; Bassler, B. L., "Functional determinants of the quorum-sensing non-coding RNAs and their roles in target regulation." Embo Journal 2013, 32 (15), 2158-2171.
O'Loughlin, C. T.; Miller, L. C.; Siryaporn, A.; Drescher, K.; Semmelhack, M. F.; Bassler, B. L., "A quorum-sensing inhibitor blocks Pseudomonas aeruginosa virulence and biofilm formation." Proceedings of the National Academy of Sciences of the United States of America 2013, 110 (44), 17981-17986.
Ng, W.-L.; Perez, L.; Cong, J.; Semmelhack, M. F.; Bassler, B. L., "Broad Spectrum Pro-Quorum-Sensing Molecules as Inhibitors of Virulence in Vibrios." Plos Pathogens 2012, 8 (6).
Perez, L. J.; Ng, W.-L.; Marano, P.; Brook, K.; Bassler, B. L.; Semmelhack, M. F., "Role of the CAI-1 Fatty Acid Tail in the Vibrio cholerae Quorum Sensing Response." Journal of Medicinal Chemistry 2012, 55 (22), 9669-9681.
Rutherford, S. T.; Bassler, B. L., "Bacterial quorum sensing: its role in virulence and possibilities for its control." Cold Spring Harbor perspectives in medicine 2012, 2 (11).
Shao, Y.; Bassler, B. L., "Quorum-sensing non-coding small RNAs use unique pairing regions to differentially control mRNA targets." Molecular Microbiology 2012, 83 (3), 599-611.
an Kessel, J. C.; Rutherford, S. T.; Shao, Y.; Utria, A. F.; Bassler, B. L., "The master regulators AphA and LuxR control the Vibrio harveyi quorum-sensing regulon: analysis of their individual and combined effects." Journal of Bacteriology 2012.
Wei, Y.; Ng, W. L.; Cong, J.; Bassler, B. L., "Ligand and antagonist driven regulation of the Vibrio cholerae quorum-sensing receptor CqsS." Mol Microbiol 2012, 83 (6), 1095-108.
Rutherford, S. T.; van Kessel, J. C.; Shao, Y.; Bassler, B. L., "AphA and LuxR/HapR reciprocally control quorum sensing in vibrios." Genes & Development 2011, 25 (4), 397-408.
Wei, Y.; Perez, L. J.; Ng, W.-L.; Semmelhack, M. F.; Bassler, B. L., "Mechanism of Vibrio cholerae Autoinducer-1 Biosynthesis." Acs Chemical Biology 2011, 6 (4), 356-365.
Chen, G.; Swem, L. R.; Swem, D. L.; Stauff, D. L.; O'Loughlin, C. T.; Jeffrey, P. D.; Bassler, B. L.; Hughson, F. M., "A Strategy for Antagonizing Quorum Sensing." Molecular Cell 2011, 42 (2), 199-209.
Drescher, K.; Shen, Y.; Bassler, B. L.; Stone, H. A., "Biofilm streamers cause catastrophic disruption of flow with consequences for environmental and medical systems." Proceedings of the National Academy of Sciences of the United States of America 2013, 110 (11), 4345-4350.
Ng, W.-L.; Perez, L. J.; Wei, Y.; Kraml, C.; Semmelhack, M. F.; Bassler, B. L., "Signal production and detection specificity in Vibrio CqsA/CqsS quorum-sensing systems." Molecular Microbiology 2011, 79 (6), 1407-1417.
Bassler, B. L., "Small Cells-Big Future." Molecular Biology of the Cell 2010, 21 (22), 3786-3787.
Ng, W.-L.; Wei, Y.; Perez, L. J.; Cong, J.; Long, T.; Koch, M.; Semmelhack, M. F.; Wingreen, N. S.; Bassler, B. L., "Probing bacterial transmembrane histidine kinase receptor-ligand interactions with natural and synthetic molecules." Proceedings of the National Academy of Sciences of the United States of America 2010, 107 (12), 5575-5580.
Teng, S.-W.; Wang, Y.; Tu, K. C.; Long, T.; Mehta, P.; Wingreen, N. S.; Bassler, B. L.; Ong, N. P., "Measurement of the Copy Number of the Master Quorum-Sensing Regulator of a Bacterial Cell." Biophysical Journal 2010, 98 (9), 2024-2031.
Tu, K. C.; Long, T.; Svenningsen, S. L.; Wingreen, N. S.; Bassler, B. L., "Negative Feedback Loops Involving Small Regulatory RNAs Precisely Control the Vibrio harveyi Quorum-Sensing Response." Molecular Cell 2010, 37 (4), 567-579.