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Ronald K. Taylor, Ph.D.

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Vibrio cholerae is a gram-negative bacterium that colonizes the human intestinal tract causing severe, potentially lethal, diarrhea in infected individuals. V. cholerae represents a paradigm of bacterial pathogens. It elaborates a plethora of virulence factors including a potent exotoxin, adherence colonization factors, secreted enzymes, and additional toxins that contribute to its pathogenesis. The expression of the genes that encode these factors is exquisitely coordinated in response to the environment the bacterium encounters, such as certain regions of the host intestine. All of these mechanisms represent models for bacterial pathogenesis and interaction with the host in general. Our laboratory focuses on the molecular mechanisms of adherence with respect to colonization, protein secretion with respect to the elaboration of adherence factors and toxin, and coordinate expression of the corresponding genes. Our goals are to understand the processes in enough detail to design better methods to control infection by defining immunogens for improved vaccine development, improving ways to grow strains for manufacture of killed whole cell vaccines, and by identifying new targets to be considered for the design of novel antibiotics.

The research projects in our lab can be divided into two broad areas. The first deals with interaction between the bacterium and the host. Bacteria colonize hosts through the use of surface appendages termed fimbriae or pili. Vibrio cholerae potentially utilizes several pili types and outer membrane proteins for this process. All of these represent potential immunogens. We have focused on a pilus termed TCP for toxin coregulated pilus. For this structure, we employ molecular biology and immunology techniques to investigate the function of specific domains in the colonization process, and the efficacy for their use as vaccine components. Aspects of the pilus study also involve the macromolecular assembly of this structure by studying the functions of various cloned gene products. We are finding that the process requires novel molecules that have homologs in various extracellular protein secretion processes and which may be inhibitable by antimicrobial compounds. Another surface component that has potential as an immunogen is the LPS layer that covers the surface of the bacterium. Monoclonal antibodies are being used to investigate potential protective epitopes on this structure.

The second major area of investigation is to understand the mechanisms by which V. cholerae senses the environment and induces expression of virulence genes. Specifically we are investigating the mechanism of activation of the tcp genes that encode the pilus, and the ctx genes that encode the cholera toxin. This activation works through a regulatory cascade that includes a membrane sensing and DNA binding protein termed ToxR which in turn regulates the expression of a cytoplasmic activator protein, ToxT, that is also required for expression of many virulence genes. We are employing genetic techniques such as challenge phage and gene fusion technology to understand very specific details of how these regulatory proteins act at their respective promoters, and how they actually sense environmental signals. This work should lead to an understanding of the signals that trigger gene expression and how the process can be altered during infection. Visit the Molecular Pathogenesis Web site or the Taylor Lab for more complete information regarding the Taylor Lab and collaborative projects with other labs.