PSEUDOMONAS AERUGINOSA ADHESION TO MUC1 MUCIN

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Mucus lining the airway luminal surface serves as a primary physicochemical barrier through its visco-elastic property. This property of airway mucus is determined mainly by both the quality and concentrations of mucous glycoproteins or mucins that are secreted by the underlying epithelial cells. Mucins are high molecular mass glycoproteins in which about 80% of the molecular weight is contributed by carbohydrates whose detailed structures are still unclear. Recently it has been shown that a type of mucins called MUC1 mucins which were first identified on the surface of human breast and pancreatic cancer cells are also present in normal epithelial tissues including airway epithelium. The role of these cell surface mucins in the airway, however, is not known. Using a primary hamster tracheal surface epithelial (HTSE) cell culture system which has been relatively well characterized in terms of the biochemistry and pharmacology of mucins, we intended to understand the role of these MUC1 gene at confluence, and its deduced amino acid sequence revealed that it consists of 676 amino acids which contain the following four major domains: (1) N-terminal signal peptide, (2) the extracellular domain with 12 tandem repeats of 20 amino acids, (3) the transmembrane domain, and (4) the C-terminal cytoplasmic tail. The presence of tyrosine-phosphorylation consensus motifs in the cytoplasmic tail is very interesting and seems to suggest a potential role in signal transduction. Since secreted mucins in the airway are known to bind to bacteria , especially Pseudomonas aeruginosa (PA), a major bacterial strain responsible for various clinical complications found in patients with cystic fibrosis, we have mucins on the surface of an epithelial cell line increased PA adhesion to these epithelial cells. We hypothesize that MUC1 mucins on the surface of airway epithelial cells serve as a receptor for PA, and adhesion of PA to these MUC1 mucins lead to some as yet unknown epithelial responses which are likely associated with PA-induced airway inflammation. In this proposal, we will first confirm this finding that MUC1 mucins are PA adhesion sites, and then investigate the molecular basis of PA adhesion to MUC1 mucins. Successful completion of this study will provide a basis to study the epithelial responses to bacterial adhesion which may be crucially important in airway inflammation in general, and cystic fibrosis in particular.