Transfer of a cathelicidin peptide antibiotic gene restores bacterial killing in a cystic fibrosis xenograft model.
Recent studies suggest that the gene defect in cystic fibrosis (CF) leads to a breach in innate immunity. We describe a novel genetic strategy for reversing the CF-specific defect of antimicrobial activity by transferring a gene encoding a secreted cathelicidin peptide antibiotic into the airway epithelium grown in a human bronchial xenograft model. The airway surface fluid (ASF) from CF xenografts failed to kill Pseudomonas aeruginosa or Staphylococcus aureus. Partial reconstitution of CF transmembrane conductance regulator expression after adenovirus-mediated gene transfer restored the antimicrobial activity of ASF from CF xenografts to normal levels. Exposure of CF xenografts to an adenovirus expressing the human cathelicidin LL-37/hCAP-18 increased levels of this peptide in the ASF three- to fourfold above the normal concentrations, which were equivalent in ASF from CF and normal xenografts before gene transfer. The increase of LL-37 was sufficient to restore bacterial killing to normal levels. The data presented describe an alternative genetic approach to the treatment of CF based on enhanced expression of an endogenous antimicrobial peptide and provide strong evidence that expression of antimicrobial peptides indeed protects against bacterial infection.
Bals
R
R
Department of Medicine and Molecular and Cellular Engineering, Institute for Human Gene Therapy, The Wistar Institute, Philadelphia, Pennsylvania 19104-4268, USA.
Weiner
D J
DJ
Meegalla
R L
RL
Wilson
J M
JM
D000818:Animals; D000900:Anti-Bacterial Agents / Q000096:biosynthesis / Q000276:immunology*; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000276:immunology*; D001980:Bronchi / Q000166:cytology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000276:immunology*; D054804:Cathelicidins; D017690:Cell Transplantation; D002645:Chickens; D003550:Cystic Fibrosis / Q000276:immunology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D006367:HeLa Cells; D006801:Humans; D011550:Pseudomonas aeruginosa / Q000254:growth & development / Q000276:immunology; D013211:Staphylococcus aureus / Q000254:growth & development / Q000276:immunology; D013552:Swine; D014183:Transplantation, Heterologous
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; C505032:CFTR protein, human; D002352:Carrier Proteins; D054804:Cathelicidins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator