BACKGROUND Increasing the activity of defective cystic fibrosis transmembrane conductance regulator (CFTR) protein is a potential treatment for cystic fibrosis. METHODS We conducted a randomized, double-blind, placebo-controlled trial to evaluate ivacaftor (VX-770), a CFTR potentiator, in subjects 12 years of age or older with cystic fibrosis and at least one G551D-CFTR mutation. Subjects were randomly assigned to receive 150 mg of ivacaftor every 12 hours (84 subjects, of whom 83 received at least one dose) or placebo (83, of whom 78 received at least one dose) for 48 weeks. The primary end point was the estimated mean change from baseline through week 24 in the percent of predicted forced expiratory volume in 1 second (FEV1). RESULTS The change from baseline through week 24 in the percent of predicted FEV1 was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P<0.001). Effects on pulmonary function were noted by 2 weeks, and a significant treatment effect was maintained through week 48. Subjects receiving ivacaftor were 55% less likely to have a pulmonary exacerbation than were patients receiving placebo, through week 48 (P<0.001). In addition, through week 48, subjects in the ivacaftor group scored 8.6 points higher than did subjects in the placebo group on the respiratory-symptoms domain of the Cystic Fibrosis Questionnaire–revised instrument (a 100-point scale, with higher numbers indicating a lower effect of symptoms on the patient’s quality of life) (P<0.001). By 48 weeks, patients treated with ivacaftor had gained, on average, 2.7 kg more weight than had patients receiving placebo (P<0.001). The change from baseline through week 48 in the concentration of sweat chloride, a measure of CFTR activity, with ivacaftor as compared with placebo was −48.1 mmol per liter (P<0.001). The incidence of adverse events was similar with ivacaftor and placebo, with a lower proportion of serious adverse events with ivacaftor than with placebo (24% vs. 42%). CONCLUSIONS Ivacaftor was associated with improvements in lung function at 2 weeks that were sustained through 48 weeks. Substantial improvements were also observed in the risk of pulmonary exacerbations, patient-reported respiratory symptoms, weight, and concentration of sweat chloride.
Bacterial pathogens frequently use protein secretion to mediate interactions with their hosts. Here we found that a virulence locus (HSI-I) of Pseudomonas aeruginosa encodes a protein secretion apparatus. The apparatus assembled in discrete subcellular locations and exported Hcp1, a hexameric protein that forms rings with a 40 angstrom internal diameter. Regulatory patterns of HSI-I suggested that the apparatus functions during chronic infections. We detected Hcp1 in pulmonary secretions of cystic fibrosis (CF) patients and Hcp1-specific antibodies in their sera. Thus, HSI-I likely contributes to the pathogenesis of P. aeruginosa in CF patients. HSI-I-related loci are widely distributed among bacterial pathogens and may play a general role in mediating host interactions.Pseudomonas aeruginosa is an opportunistic pathogen that chronically infects the lungs of >80% of cystic fibrosis patients and is the primary cause of morbidity and mortality in these patients (1). A distinguishing feature of the bacterium is its high degree of versatility, which provides P. aeruginosa sufficient phenotypic plasticity to form both acute and chronic infections in humans (2,3). The choice between these disparate life-styles is governed by global virulence regulators, including RetS (regulator of exopolysaccharide and type III secretion) (4) and LadS (lost adherence sensor) (5). RetS and LadS reciprocally regulate virulence determinants such as type III secretion, which is RetS-activated and LadS-repressed, as well as exopolysaccharide production, which is RetS-repressed and LadS-activated. These virulence factors are important in acute and chronic infections, respectively.In addition to characterized virulence pathways, microarray analyses indicated that RetS and LadS reciprocally regulated a functionally uncharacterized virulence locus (Fig. 1). Consistent with its regulatory patterns by RetS and LadS, the virulence locus was required for chronic P. aeruginosa infection of the rat lung ( Fig. 1) homologous to a group of genes found in many Gram-negative proteobacteria that have been termed the IcmF-associated homologous protein (IAHP) cluster (7). P. aeruginosa encodes two other IAHP-related loci elsewhere in its genome; however, these loci were not regulated by either RetS or LadS and have no known role in virulence (Fig. 1). An overview of the distribution and genetic constituents of IAHP loci is shown (table S1).The IAHP-related locus of Vibrio cholerae, which the authors have designated a type VI secretion system, mediates cytotoxicity in phagocytic cells and is required for the extracellular secretion of four proteins lacking canonical hydrophobic amino-terminal signal sequences (8). We postulated that the RetS-and LadS-regulated IAHP locus in P. aeruginosa could play a similar role in extracellular protein targeting. To test this hypothesis, we activated expression of the locus in P. aeruginosa PAO1 by deleting retS. Comparison of the supernatant fractions of ΔretS and wild-type revealed that a small protein (M r ~1...
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