Cystic fibrosis: a mucosal immunodeficiency syndrome

Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) functions as a channel that regulates the transport of ions and the movement of water across the epithelial barrier. Mutations in CFTR, which form the basis for the clinical manifestations of cystic fibrosis, affect the epithelial innate immune function in the lung, resulting in exaggerated and ineffective airway inflammation that fails to eradicate pulmonary pathogens. Compounding the effects of excessive neutrophil recruitment, the mutant CFTR channel does not transport antioxidants to counteract neutrophil-associated oxidative stress. Whereas mutant CFTR expression in leukocytes outside of the lung does not markedly impair their function, the expected regulation of inflammation in the airways is clearly deficient in cystic fibrosis. The resulting bacterial infections, which are caused by organisms that have substantial genetic and metabolic flexibility, can resist multiple classes of antibiotics and evade phagocytic clearance. The development of animal models that approximate the human pulmonary phenotypes-airway inflammation and spontaneous infection-may provide the much-needed tools to establish how CFTR regulates mucosal immunity and to test directly the effect of pharmacologic potentiation and correction of mutant CFTR function on bacterial clearance.

Figure 1

Altered TLR expression and signaling in the cystic fibrosis (CF) epithelium. Expression of TLR2 and TLR5 at the apical surface is increased, whereas TLR4 expression is restricted to the endosome. NF-κB in cystic fibrosis airway epithelial cells is constitutively activated, resulting in the production of inflammatory cytokines, such as IL-8 and GM-CSF, and the recruitment of PMNs independently of TLR’s interaction with the adaptor protein MyD88. After infection, bacterial PAMPs further increase NF-κB signaling through activation of TLR-MyD88 signaling. Intracellular TLR4 activation of Trif from the endosome is impaired, preventing interferon regulatory factor 3 (IRF3) translocation to the nucleus and the activation of type I IFN gene products, which are required for the activation of dendritic cells (DCs) and the clearance of some cystic fibrosis–related pathogens.

Figure 2

Increased oxidative stress in the cystic fibrosis airway. Constitutive NF-κB–mediated production of chemokines, including IL-8, leads to PMN recruitment, which persist in the airway, increasing the oxidative burden in the lung. Oxidative stress activates MAPK signaling pathways in the cystic fibrosis epithelium, amplifying the production of IL-8 and, therefore, recruiting additional PMNs. Mutant CFTR in the epithelial cells is unable to channel the antioxidants GSH and SCN⁻ into the airway, limiting its ability to counteract the oxidative stress. Because SCN⁻ also has antimicrobial properties, bacterial killing in the airway is diminished as well.

Figure 3

Adaptation of inhaled bacteria to the cystic fibrosis airway. Inhaled bacteria expressing flagella, pili and a type 3 secretion system (T3SS) aggregate within the cystic fibrosis lung, resulting in the formation of biofilm. Within the biofilm, bacteria lose flagella, pili and the T3SS, increase alginate production, release CpG DNA and express a diverse range of virulence factors promoting evasion of the host immune system. P. aeruginosa also releases outer membrane vesicles containing Cif, a protein that inhibits the recycling of CFTR in the host. Furthermore, the lipid A structure of the LPS is altered through the addition of palmitate and aminoarabinose, resulting in increased antibiotic (Ab) resistance and increased induction of IL-8 production by host cells.