Pseiulomonus aeruginosa (PA) is an opportunistic bacterial pathogen responsible for a number of idinically important lung diseases including pneumonia and cystic fibrosis (CF). In the case of CF, .he major j jcause of morbidity and mortality among afflicted patients is airway obstruction due to the presence of thick and tenacious mucus that becomes heavily infected with PA. Because PA exposure occurs in therespiratory system of both normal and CF individuals, """"""""selective""""""""'infection by this pathogen among CF pi.tients suggests the presence of a disease-causing mechanism that is not present in non-CF airways. A number of di ffeivnt theories have been proposed to account for the etiology of CF. Our laboratory made theinteresting observation that MUC1 mucin on the surface of airway epithelial cells is a specific binding site for PA mediated through bacterial flagellin. The structureof the MUC1 glycoprotein suggests that it acts as a receptor to transmit signals intracellularly following interaction with flagellin. Using mice genetically modified to block MUC1 expression (MUC1 knockout mice), our preliminarystudies showed that, compared with wild type mice, Mud knockout animals exhibited increased PA clearance from the lungs and greater recruitment of airway leukocytes and higher levels of the proinflammatory cytokincs in bronchoalveolar lavuge fluid following PA flagellin stimulation. Interestingly,TLR5 is another cell surface receptor tha generates an intracellular signaling pathway following binding to flagellin. Based on this similarity, we conducted additional experiments to investigate the functional relationshipbetween 'ViUCl and TLR5. We observed that expression of MUC1 inhibited the flagellin-TLR5 signaling pathway in normal lung cells but not CF airway epithelial cells. Based on these results, we formed the hypothesis thai MUC1 is an anti- inflamrnatory cell surface receptor that acts, at least in part, through antagonism of flagellin-'1 LR5 signaling. In this proposal, we will test our theory by determining the mechanisms by which MUC1 attenuatesT1..R5 signal transduction. Successful completion of this project will provide important insights for the role of MIJC1 in inflammation, innate immunity, and the early stages of PA infection in CF.
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