Neutrophil Defect and Lung Pathogen Selection in Cystic Fibrosis.

Cystic fibrosis (CF) is a life-threatening genetic disorder caused by mutations in the CF Transmembrane-conductance Regulator (CFTR) chloride channel. Clinically, over 90% of CF patients succumb to pulmonary complications precipitated by chronic bacterial infections, predominantly by Pseudomonas aeruginosa (PA) and Staphylococcus aureus (SA). Despite the well-characterized gene defect and clearly defined clinical sequelae of CF, the critical link between the chloride channel defect and the host defense failure against these specific pathogens has not been established. Previous research from us and others has uncovered that neutrophils from CF patients are defective in phagosomal production of hypochlorous acid (HOCl), a potent microbicidal oxidant. Here we report our studies to investigate if this defect in HOCl production provides PA and SA with a selective advantage in CF lungs. A polymicrobial mixture of CF pathogens (PA and SA) and non-CF pathogens (Streptococcus pneumoniae (SP), Klebsiella pneumoniae (KP), and Escherichia coli (EC)) was exposed to varied concentrations of HOCl. The CF pathogens withstood higher concentrations of HOCl than did the non-CF pathogens. Neutrophils derived from F508del-CFTR HL-60 cells killed PA less efficiently than did the wild-type counterparts in the polymicrobial setting. After intratracheal challenge in wild-type and CF mice, the CF pathogens outcompeted the non-CF pathogens and exhibited greater survival in the CF lungs. Taken together, these data indicate that reduced HOCl production due to the absence of CFTR function creates an environment in CF neutrophils that provides a survival advantage to specific microbes, namely SA and PA, in the CF lungs.