Protection versus susceptibility to P. aeruginosa infection in lungs expressing wild-type or mutant CFTR. (A) Proposed factors responding to P. aeruginosa in the airway of humans with intact, wild-type CFTR. Some of the bacteria in normal mucus with properly unfolded mucins bind to CFTR in the plasma membrane, initiating rapid (2–15 min) IL-1 release; the resulting IL-1 triggers autocrine or paracrine signaling through the IL-1 receptor. Bacteria binding to CFTR also initiates formation of lipid rafts and recruitment of caveolin, major vault protein (MVP), and other proteins to the rafts; this is followed by bacterial internalization. These processes leads to MyD88-dependent activation and nuclear translocation of NF-κB and regulated inflammatory responses involving production of IL-6 and IL-8 and increases in ICAM-1 and Gro-1 (CXCL1), all of which participate in recruitment of polymorphonuclear neutrophils (PMN) to the airway mucosa. The remaining, viable P. aeruginosa are phagocytosed and killed, and those entrapped within epithelial cells are carried out in the mucus. (B) On the CF airway surface, lack of functional CFTR, such as the ΔF508 variant that is unable to make it to the plasma membrane, leaves the P. aeruginosa bacteria trapped in the mucus, which is dehydrated and more viscous because of the compacted mucins released from the secretory granules of goblet cells. PMN recruitment does occur, but in a dysregulated, uncoordinated, and slower fashion, and when the PMN do arrive their ability to phagocytose the P. aeruginosa cells trapped within the airway mucus is poor. The frustrated phagocytosis can lead to release of granule contents containing toxic factors. The PMN undergo necrosis instead of apoptosis, and this results in a failure to clear bacteria and resolve inflammation. The chronic infection is perpetuated by an ineffective adaptive immune response, allowing the progression of chronic infection, inflammation, and destruction of lung tissue.