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The ΔF508 CFTR mutation, which is the commonest cause of cystic fibrosis (CF), has the highest frequency of any genetic mutation among Caucasians of central European origin. Persistence of a mutation suggests that heterozygosity for this mutation imparts some genetic advantage. We hypothesized that heterozygosity provides a selective survival advantage during influenza pneumonitis, as a result of reduced pulmonary edema formation. The aim of this project was to determine the effect of the ΔF508 CFTR mutation on the susceptibility to influenza in a mouse model. 8-12 wk old wild-type (CFTR+/+), heterozygous (CFTR+/-), or homozygous knockout (CFTR-/-) mice were infected intra-nasally with a mouse-adapted H1N1 influenza virus. Mock infections with virus diluent served as an infection control. Body weight changes were measured daily in individually-marked mice. Other disease outcome variables were measured in mice sacrificed at 2 or 6 days post-infection (d.p.i.), to determine whether disease severity is reduced in ΔF508 heterozygous mice. At these time points, alveolar fluid clearance rate (an in vivo measure of respiratory epithelial ion transport capacity), viral replication in lung homogenates, and lung water content (wet:dry ratio) were measured. Following influenza infection, ΔF508 heterozygotes show significantly delayed mortality, which is associated with significantly reduced AFC impairment at 2 and 6 d.p.i., and absence of pulmonary edema at 2 d.p.i. (normal wet;dry weight ratio). Delayed mortality did not result from either reduced weight loss or reduced viral replication in lungs of ΔF508 heterozygotes. ΔF508 heterozygous mice demonstrate reduced lung injury and improved survival following infection with a lethal dose of mouse-adapted influenza A virus. This finding suggests that heterozygosity for the ΔF508 CFTR mutation may similarly provide a selective survival advantage during influenza pneumonitis in man.