Human beta-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis.
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 beta-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.
Goldman
M J
MJ
Department of Medicine, The University of Pennsylvania Medical Center, Philadelphia 19104, USA.
Anderson
G M
GM
Stolzenberg
E D
ED
Kari
U P
UP
Zasloff
M
M
Wilson
J M
JM
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D016375:Antisense Elements (Genetics) / Q000494:pharmacology; D001483:Base Sequence; D001798:Blood Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D001980:Bronchi / Q000737:chemistry* / Q000473:pathology / Q000637:transplantation; D003550:Cystic Fibrosis / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D023082:Defensins; D006801:Humans; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D012965:Sodium Chloride / Q000378:metabolism / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D023083:beta-Defensins
D000900:Anti-Bacterial Agents; D016375:Antisense Elements (Genetics); D001798:Blood Proteins; C406407:DEFB1 protein, human; D023082:Defensins; D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D023083:beta-Defensins; D012965:Sodium Chloride