Human β-Defensin-1 Is a Salt-Sensitive Antibiotic in Lung That Is Inactivated in Cystic Fibrosis

TLDR

A human bronchial xenograft model was used to characterize the molecular basis for the previously described defect in bacterial killing present in the cystic fibrosis lung. The authors isolated a full‑length hBD‑1 clone and employed a human bronchial xenograft model to investigate bacterial killing defects in CF. CF airway surface fluid had high NaCl and lacked bacterial killing, but adenoviral vectors restored activity; hBD‑1, expressed throughout respiratory epithelia, shows salt‑dependent antimicrobial activity against *P.

Abstract

A human bronchial xenograft model was used to characterize the molecular basis for the previously described defect in bacterial killing that is present in the cystic fibrosis (CF) lung. Airway surface fluid from CF grafts contained abnormally high NaCl and failed to kill bacteria, defects that were corrected with adenoviral vectors. A full-length clone for the only known human β-defensin (i.e., hBD-1) was isolated. This gene is expressed throughout the respiratory epithelia of non-CF and CF lungs, and its protein product shows salt-dependent antimicrobial activity to P. aeruginosa. Antisense oligonucleotides to hBD-1 ablated the antimicrobial activity in airway surface fluid from non-CF grafts. These data suggest that hBD-1 plays an important role in innate immunity that is compromised in CF by its salt-dependent inactivation.