Focus

Cell-to-Cell Communication in Bacteria

Research

The research in my laboratory focuses on the molecular mechanisms that bacteria use for intercellular communication. Our goal is to understand how bacteria detect multiple environmental cues, and how the integration and processing of this information results in the precise regulation of gene expression.

The bacterial communication phenomenon that we study is called quorum sensing, which is a process that allows bacteria to communicate using secreted chemical signaling molecules called autoinducers. This process enables a population of bacteria to collectively regulate gene expression and, therefore, behavior. In quorum sensing, bacteria assess their population density by detecting the concentration of a particular autoinducer, which is correlated with cell density. This "census-taking" enables the group to express specific genes only at particular population densities. Quorum sensing is widespread; it occurs in numerous Gram-negative and Gram-positive bacteria. In general, processes controlled by quorum sensing are ones that are unproductive when undertaken by an individual bacterium but become effective when undertaken by the group. For example, quorum sensing controls bioluminescence, secretion of virulence factors, sporulation, and conjugation. Thus, quorum sensing is a mechanism that allows bacteria to function as multi-cellular organisms.

We have shown that the model luminous bacterium Vibrio harveyi and the related pathogen Vibrio cholerae each produce two different autoinducers, called AI-1 and AI-2, each of which is detected by its own sensor protein. Both sensors transduce information to a shared integrator protein to control the output, light emission in V. harveyi and virulence in V. cholerae. We have cloned the genes for signal production, detection and response in both species and have shown that the mechanism of signal relay is a phosphorylation/dephosphorylation cascade. Our recent studies combining genetics and bioinformatics (in collaboration with the Wingreen lab) show that the small RNA chaperone protein Hfq, together with multiple small regulatory RNAs (sRNAs), act at the center of these quorum sensing cascades. They function as an ultrasensitive regulatory switch that controls the critical transition into and out of quorum sensing mode.

V. harveyi and V. cholerae use the AI-1 quorum sensing circuit for intra-species communication and the AI-2 quorum sensing circuit for inter-species communication. To investigate the mechanism of AI-2 signaling, we constructed mutants and cloned the gene responsible for AI-2 production from several bacteria. The gene we identified in each case is highly homologous, and we named it luxS. We found that luxS homologues and AI-2 production are widespread in the bacterial world, suggesting that communication via an AI-2 signal response system could be a common mechanism that bacteria employ for inter-species interaction in natural environments. We determined the biosynthetic pathway for AI-2 production as well as the AI-2 identity by solving the crystal structures of the V. harveyi and S. typhimurium sensor proteins in complex with their cognate AI-2 signals. The structural work was performed in collaboration with the Hughson lab. The V. harveyi AI-2 is a furanosylborate diester. Finding boron in the active molecule was surprising because boron, while widely available in nature has almost no known role in biology. The S. typhimurium crystal showed that its receptor binds a chemically distinct AI-2 that lacks borate. Importantly, the active signal molecules spontaneously inter-convert upon release from their respective receptors, revealing a surprising level of sophistication in the chemical lexicon used by bacteria for inter-species cell-cell communication.

Finally, we are focused on developing molecules that are structurally related to AI-2. Such molecules have potential use as anti-microbial drugs aimed at bacteria that use AI-2 quorum sensing to control virulence. Similarly, the biosynthetic enzymes involved in AI-2 production and the AI-2 detection apparatuses are viewed as potential targets for novel anti-microbial drug design.

Biography

Bonnie L. Bassler is a member of the National Academy of Sciences and the American Academy of Arts and Sciences. She is a Howard Hughes Medical Institute Investigator and the Squibb Professor of Molecular Biology at Princeton University. Bassler received a B.S. in Biochemistry from the University of California at Davis, and a Ph.D. in Biochemistry from the Johns Hopkins University. She performed postdoctoral work in Genetics at the Agouron Institute, and she joined the Princeton faculty in 1994. The research in her laboratory focuses on the molecular mechanisms that bacteria use for intercellular communication. This process is called quorum sensing. Bassler’s research is paving the way to the development of novel therapies for combating bacteria by disrupting quorum-sensing-mediated communication. At Princeton, Dr. Bassler teaches both undergraduate and graduate courses. Dr. Bassler directed the Molecular Biology Graduate Program from 2002-2008 and she currently chairs Princeton University’s Council on Science and Technology which has revamped the science curriculum for humanists. Bassler is a passionate advocate for diversity in the sciences and she is actively involved in and committed to educating lay people in science. Dr. Bassler was awarded a MacArthur Foundation Fellowship in 2002. She was elected to the American Academy of Microbiology in 2002 and made a fellow of the American Association for the Advancement of Science in 2004. She was given the 2003 Theobald Smith Society Waksman Award and she is the 2006 recipient of the American Society for Microbiology’s Eli Lilly Investigator Award for fundamental contributions to microbiological research. In 2008, Bassler was given Princeton University’s President’s Award for Distinguished Teaching. She is the 2009 recipient of the Wiley Prize in Biomedical Science for her paradigm-changing scientific research. She is the 2011 recipient of the National Academies’ Richard Lounsbery Award. She is the 2012 UNESCO-L’Oreal Woman in Science for North America. In 2012, Bassler was also elected to the Royal Society and to the American Philosophical Society. Bassler was the President of the American Society for Microbiology in 2010-2011. She is currently the Chair of the American Academy of Microbiology Board of Governors. She is a member of the National Science Board and was nominated to that position by President Barack Obama. The Board oversees the NSF and prioritizes the nation’s research and educational priorities in science, math and engineering. She was an editor for a decade for Molecular Microbiology, and is currently an editor of mBio, and Chief Editor of Annual Reviews of Genetics. She is an associate editor for Cell, Proceedings of the National Academy of Sciences, Journal of Bacteriology, and other journals. Among other duties, she serves on the National Academies Board on Life Sciences, the Howard Hughes Medical Institute Science Education Committee, and Discovery Communications’ Science Channel Scientific Advisory Board. She serves on oversight, grant, fellowship, and award panels for the National Academies of Sciences, National Institutes of Health, National Science Foundation, American Society for Microbiology, American Academy of Microbiology, Keck Foundation, Burroughs Wellcome Trust, Jane Coffin Childs Fund, PEW Charitable Trust, Gordon and Betty Moore Foundation, and the MIT Whitehead Institute.

Honors & Awards