Role of the cystic fibrosis transmembrane conductance regulator in innate immunity to Pseudomonas aeruginosa infections

Chronic Pseudomonas aeruginosa infection occurs in 75-90% of patients with cystic fibrosis (CF), It is the foremost factor in pulmonary function decli ne and early mortality. A connection has been made between mutant or missin g CF transmembrane conductance regulator (CTTR) in lung epithelial cell mem branes and a failure in innate immunity leading to initiation of P. aerogin osa infection. Epithelial cells use CFTR as a receptor for internalization of P. aeruginosa via endocytosis and subsequent removal of bacteria from th e airway, In the absence of functional CFTR, this interaction does not occu r, allowing for increased bacterial loads in the lungs. Binding occurs betw een the outer core of the bacterial lipopolysaccharide and amino acids 108- 117 in the first predicted extracellular domain of CFTR, In experimentally infected mice, inhibiting CFTR-mediated endocytosis of P. aeruginosa by inc lusion in the bacterial inoculum of either free bacterial lipopolysaccharid e or CFTR peptide 108-117 resulted in increased bacterial counts in the lun gs. CFTR is also a receptor on gastrointestinal epithelial cells for Salmon ella enterica serovar Typhi, the etiologic agent of typhoid fever. There wa s a significant decrease in translocation of this organism to the gastroint estinal submucosa in transgenic mice that are heterozygous carriers of a mu tant Delta F508 CFTR allele, suggesting heterozygous CFTR carriers may have increased resistance to typhoid fever. The identification of CTTR as a rec eptor for bacterial pathogens could underlie the biology of CF lung disease and be the basis for the heterozygote advantage for carriers of mutant all eles of CFTR.