Of the various toxins and virulence-related factors produced by Bordetella pertussis, only one has been demonstrated to reproduce the specific respiratory tract cytopathology of the pertussis syndrome. That molecule is tracheal cytotoxin (TCT), a low molecular weight glycopeptide released by B. pertussis during normal growth. This laboratory's research has centered on characterizing TCT in molecular detail and relating those studies to the disease states caused by infections with Bordetella spp. Other laboratories' work on TCT-like molecules (muramyl peptides) has provided clues to TCT's mechanism of action and its role in a variety of biological activities. This application for renewed grant support continues with the long-term goal of understanding how this toxin contributes to the pathology associated with pertussis. During the three-year period of this project, the following two major research questions will be addressed: I. How does the molecular structure of TCT relate to its biological function? Enzymatic cleavage, chemical modification, and peptide synthesis are planned to generate a diverse collection of TCT structural analogs. Detailed structure/function mapping with these molecules will help define what portions of TCT are essential (or unimportant) for toxicity and/or binding to host cells. II. What is the molecular basis for TCT-target cell specificity? These experiments will test the hypothesis that TCT binds to susceptible host cells via a specific receptor. Classical ligand-receptor binding experiments with cell cultures and organ cultures are designed to evaluate binding specificity, ligand structural requirements, target cell specificity, and the fate of bound ligand.
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