Transgenic cystic fibrosis mice exhibit reduced early clearance of Pseudomonas aeruginosa from the respiratory tract

The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) has bee n proposed to be an epithelial cell receptor for Pseudomonas aeruginosa inv olved in bacterial internalization and clearance from the lung. We evaluate d the role of CFTR in clearing A aeruginosa from the respiratory tract usin g transgenic CF mice that carried either the Delta F508 Cftr allele or an a llele with a Cftr stop codon (S489X). Intranasal application achieved P. ae ruginosa lung infection in inbred C57BL/6 Delta F508 Cftr mice, whereas Del ta F508 Cftr and S489X Cftr outbred mice required tracheal application of t he inoculum to establish lung infection. CF mice showed significantly less ingestion of LPS-smooth P. aeruginosa by lung cells and significantly great er bacterial lung burdens 4.5 h postinfection than C57BL/6 wild-type mice. Microscopy of infected mouse and rhesus monkey tracheas clearly demonstrate d ingestion of P. aeruginosa by epithelial cells in wild-type animals, most ly around injured areas of the epithelium. Desquamating cells loaded with A aeruginosa could also be seen in these tissues. No difference was found be tween CF and wild-type mice challenged with an LPS-rough mucoid isolate of P. aeruginosa lacking the CFTR ligand. Thus, transgenic CF mice exhibit dec reased clearance of P. aeruginosa and increased bacterial burdens in the lu ng, substantiating a key role for CFTR-mediated bacterial ingestion in lung clearance of P. aeruginosa.