Probing the role of sensory cues in the regulation of bacterial biofilm development

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PROJECT SUMMARY Bacteria have a remarkable ability to sense diverse stimuli and make regulatory decisions to elicit an appropriate response. The objective of our research program is to understand the molecular underpinnings of this cellular decision-making process during the development of three dimensional (3D) structured communities called biofilms. Biofilms represent a predominant bacterial lifestyle and are crucial for antimicrobial tolerance, virulence, and environmental persistence in diverse pathogens including multi-drug resistant Pseudomonas aeruginosa. P. aeruginosa serves as an ideal clinically relevant model system for our basic research in biofilms because it adapts to and forms biofilms in a wide variety of environments, and the biofilm matrix components in this organism are well characterized. The overarching goal of the proposed research is to define how bacteria decode and integrate sensory cues – physical, chemical and biological – over the course of the biofilm development cycle. My work has shown that light (physical cue) detected via bacteriophytochrome BphP photoreceptor mediated photo sensing and population density (biological cue) detected via RhlR mediated quorum sensing represses biofilms. Furthermore, we have discovered that nutrient availability (chemical cue) converges with quorum sensing (biological cue) to control biofilm matrix components and architecture. Over the next five years, we will build on our recent discoveries and use a multidisciplinary approach combining bacterial genetics, molecular biology, biochemistry, fluorescence microscopy, mathematical modeling, structural biology and genome-scale studies to define sensory signaling in the context of a growing biofilm. First, we will investigate how light is perceived locally and globally in heterogenous biofilms and characterize the BphP photo-sensing signaling system to understand the regulation of photo sensing in P. aeruginosa (Project 1). Second, we will dissect the CbrA-Crc nutrient-sensing pathway to learn how nutrient availability controls biofilm development (Project 2). Third, we will delineate the different ways by which RhlR mediated quorum sensing represses biofilm formation (Project 3). Finally, we will define how information from two or more distinct sensory signaling pathways are combined in the control of collective behaviors (Project 4). Our research will establish a broadly relevant framework for understanding how information encoded in diverse sensory inputs is extracted and integrated to drive collective behaviors – knowledge that is crucial for designing successful synthetic strategies to enhance or to inhibit biofilms and for developing novel therapeutic interventions.