Chronic inflammation and ensuing fibrosis result in progressive destruction of the lung following Pseudomonas aeruginosa infection in cystic fibrosis (CF), the most common lethal genetic disease of Caucasians. Specific virulence factors of P.aeruginosa facilitate its recognition of receptors available on the CF respiratory epithelial cell. Pseudomonas adhesins such as pili and flagella and certain exoproducts elicit an IL-8 response by respiratory epithelial cells which initiates the polymorphonuclear leucocyte dominated inflammation of the CF airways. A detailed analysis of the molecular interactions between the bacterial ligands and their receptors is proposed. Pili are the best characterized P.aeruginosa ligands although the precise biochemical components of the ligand-receptor binding remain undefined. Flagella are highly conserved bacterial organelles which allow for chemotaxis toward preferred carbon substrates, in vivo as well as in vitro. The significance of glycosylation of P.aeruginosa pilin will be examined to determine if this post translational modification is a common property of clinical isolates of P.aeruginosa, if glycosylation affects the adhesive properties of pill, and if glycosylated pill represent an adaptation to the host immune response. The role of flagellin as an adhesin and essential virulence factor will be explored using genetic methods to separate a motility function from a putative adhesin domain. P.aeruginosa exoproducts and central regulatory loci which enable the organism to efficiently colonize the lung will be identified. Exoproducts which are expressed specifically in response to the environment posed by the human airway epithelium will be studied and regulatory elements which coordinate their expression will be defined. Identification of the gene products expressed in the initial stages of infection may provide potential targets for therapeutic intervention. We postulate that the unique association of P.aeruginosa and the CF lung can be attributed to this genetic repertoire; the ability to attach, colonize, infect and adapt to the conditions imposed by the milieu of the airways.
