title: pH modulates the activity and synergism of the airway surface liquid antimicrobials β-defensin-3 and LL-37.
abstract: The pulmonary airways are continuously exposed to bacteria. As a first line of defense against infection, the airway surface liquid (ASL) contains a complex mixture of antimicrobial factors that kill inhaled and aspirated bacteria. The composition of ASL is critical for antimicrobial effectiveness. For example, in cystic fibrosis an abnormally acidic ASL inhibits antimicrobial activity. Here, we tested the effect of pH on the activity of an ASL defensin, human β-defensin-3 (hBD-3), and the cathelicidin-related peptide, LL-37. We found that reducing pH from 8.0 to 6.8 reduced the ability of both peptides to kill Staphylococcus aureus. An acidic pH also attenuated LL-37 killing of Pseudomonas aeruginosa. In addition, we discovered synergism between hBD-3 and LL-37 in killing S. aureus. LL-37 and lysozyme were also synergistic. Importantly, an acidic pH reduced the synergistic effects of combinations of ASL antibacterials. These results indicate that an acidic pH reduces the activity of individual ASL antimicrobials, impairs synergism between them, and thus may disrupt an important airway host defense mechanism.
authors.affiliation: Departments of Internal Medicine.
authors.forename: Mahmoud H
authors.initials: MH
authors.lastname: Abou Alaiwa
authors.affiliation: Departments of Internal Medicine.
authors.forename: Leah R
authors.initials: LR
authors.lastname: Reznikov
authors.affiliation: Departments of Internal Medicine.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Gansemer
authors.affiliation: Departments of Internal Medicine.
authors.forename: Kelsey A
authors.initials: KA
authors.lastname: Sheets
authors.affiliation: Microbiology, and.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Horswill
authors.affiliation: Departments of Internal Medicine, Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, Department of Biomedical Engineering, and.
authors.forename: David A
authors.initials: DA
authors.lastname: Stoltz
authors.affiliation: Departments of Internal Medicine.
authors.forename: Joseph
authors.initials: J
authors.lastname: Zabner
authors.affiliation: Departments of Internal Medicine, Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, Howard Hughes Medical Institute, University of Iowa, Iowa City, IA 52242 michael-welsh@uiowa.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welsh
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000819:agonists / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D011550:Pseudomonas aeruginosa / Q000254:growth & development*; D013211:Staphylococcus aureus / Q000254:growth & development*; D023083:beta-Defensins / Q000819:agonists / Q000494:pharmacology*; D054804:Cathelicidins
chemical_list: D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; C422950:DEFB103A protein, human; D023083:beta-Defensins; D054804:Cathelicidins
keywords: Pseudomonas aeruginosa; Staphylococcus aureus; cathelicidin; cystic fibrosis; host defense