The Rather Laboratory
My research program focuses on the mechanisms of cell-to-cell communication in bacteria. In recent years, a large number of studies have revealed that the ability of bacteria to communicate with each other is far more widespread and complex than previously realized. This cell-to-cell communication or signaling is mediated by molecules termed autoinducers or pheromones and include: N-acyl homoserine lactones, small peptides, and furanones. Cell-to-cell signaling is a fundamental requirement for a number of bacterial processes. Of particular medical importance is the ability of cell-to-cell signaling to regulate virulence gene expression and biofilm formation in various pathogens. Biofilms are complex microbial communities that typically form on solid surfaces. Mature biofilms form a three-dimensional structure composed of cells surrounded by a polysaccharide matrix. Within the biofilm, aqueous channels are present that act to bring in nutrients and carry out waste products. In many ways, these remarkable bacterial structures resemble a simple tissue. Biofilms are of great medical importance. First, the formation of biofilms on indwelling devices such as catheters or artificial joints often contributes to the establishment of infections. Second, cells within a biofilm are highly resistant to antibiotics. This increased resistance is due, at least in part, to physiological differences in biofilm associated cells versus cells in a planktonic state. Biofilms are also present in tissues at the site of infections. In fact, the ability of antibiotics to effectively treat many chronic infections (lung infections in cystic fibrosis patients, sinusitis, prostatitis, middle ear infections) is severely compromised by biofilm formation in tissues.
One research area is focused on cell-to-cell signaling in the urinary tract pathogen Proteus mirabilis. A unique feature of P. mirabilis is the ability swarm on solid surfaces. Swarming requires that cell differentiate from a short vegetative rod to a highly elongated, hyperflagellated swarmer cell. Our lab has identified putrescine as an extracellular signal that is required for swarmer cell differentiation. We are currently using genetic approaches to identify the response pathway(s) used to sense putrescine. In addition, genes regulated by putrescine are being identified and characterized for a role in swarming. We are also interested in the general aspects of swarming in P. mirabilis and are using genetic approaches to identify novel mutants that are impaired in this process.
A second area of interest involves quorum sensing in Acinetobacter baumannii, a non-motile, gram-negative bacterium that has emerged in recent years as an important nosocomial pathogen. A variety of infections are caused by A. baumannii including wound, bloodstream, ventilator-acquired pneumonia, and urinary tract infections. In addition, A. baumanni has been extremely problematic for United States military personnel in Iraq and Afghanistan, where this pathogen is responsible for a high number of nosocomial infections. Of particular concern with A. baumannii is the increasing frequency of multi-drug resistant (MDR) strains that leave few, if any, therapeutic options for treatment. We have identified a quorum-sensing pathway in A. baumannii that involves N-acyl homoserine lactones as signal molecules. In addition, this pathway is required for biofilm development. We are investigating the role of this pathway in global gene expression and also determining if it has a role in virulence.
Figure 1. A Proteus mirabilis speA mutant unable to produce putrescine as an extracellular signal is defective in swarming, a process that allows for rapid translocation across surfaces. Swarming is rescued near the horizontal line of cells that secrete putrescine and provide the missing signal. |
Figure 2. The top horizontal line represents Acinetobacter baumannii cells that secrete acyl homoserine lactone (AHL) quorum sensing signals. The perpendicular line of cells are Agrobacterium tumefaciens cells that contain a lacZ fusion activated by AHL signals. Activation of this gene is visualized by the blue color of the A. tumefaciens cells when they are near the AHL signal producing A. baumannii cells |
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