Alveolar macrophages (AMs) play a major role in host defense against microbial 
infections in the lung. To perform this function, these cells must ingest and 
destroy pathogens, generally in phagosomes, as well as secrete a number of 
products that signal other immune cells to respond. Recently, we demonstrated 
that murine alveolar macrophages employ the cystic fibrosis transmembrane 
conductance regulator (CFTR) Cl(-) channel as a determinant in lysosomal 
acidification (Di, A., Brown, M. E., Deriy, L. V., Li, C., Szeto, F. L., Chen, 
Y., Huang, P., Tong, J., Naren, A. P., Bindokas, V., Palfrey, H. C., and Nelson, 
D. J. (2006) Nat. Cell Biol. 8, 933-944). Lysosomes and phagosomes in murine 
cftr(-/-) AMs failed to acidify, and the cells were deficient in bacterial 
killing compared with wild type controls. Cystic fibrosis is caused by mutations 
in CFTR and is characterized by chronic lung infections. The information about 
relationships between the CFTR genotype and the disease phenotype is scarce both 
on the organismal and cellular level. The most common disease-causing mutation, 
DeltaF508, is found in 70% of patients with cystic fibrosis. The mutant protein 
fails to fold properly and is targeted for proteosomal degradation. G551D, the 
second most common mutation, causes loss of function of the protein at the 
plasma membrane. In this study, we have investigated the impact of CFTR 
DeltaF508 and G551D on a set of core intracellular functions, including 
organellar acidification, granule secretion, and microbicidal activity in the 
AM. Utilizing primary AMs from wild type, cftr(-/-), as well as mutant mice, we 
show a tight correlation between CFTR genotype and levels of lysosomal 
acidification, bacterial killing, and agonist-induced secretory responses, all 
of which would be expected to contribute to a significant impact on microbial 
clearance in the lung.