Die Aktivität der antimikrobiellen Peptide wird durch die Interaktion mit Mukus der Atemwege moduliert

Antimicrobial peptides (AMPs) and mucins are components of the airway secretions and both contribute to the innate host defense system of the lung. Antimicrobial peptides (AMPs) are effector molecules of the innate immune system, which lyse microbial cells by interaction with biomembranes. Besides their direct antimicrobial function, they have multiple roles as mediators of inflammation. The principal families of AMPs expressed in the lung are the defensins and the cathelicidins. One of the prominent physical features of AMPs is their strong positive charge at neutral pH. Mucins are macromolecular molecules with high molecular masses and belong to another class of proteins within the airway secretions. Their heavily glycosylated side chains containing sialic acid and N-acetylgalactosamine-6-sulfate determine the strong negative charge of the molecule. It was the aim of the study to investigate whether the cathelicidin LL-37 interacts with mucins and whether this interaction influences the conformation and antimicrobial activity of the AMP. The binding of mucins to the cathelicidin LL-37 coated to multiwell plates was confirmed using a lectin based assay. Circular dichoismus spectroscopy showed the adoption of an alpha-helical conformation of LL-37 in the presence of mucins. Mucin decreased the antimicrobial activity of LL-37 against Pseudomonas aeruginosa and Streptococcus pneumoniae, tested in antimicrobial assays. To investigate whether LL-37 is bound to mucins in airway secretions from human subjects, spontaneous sputum collected from cystic fibrosis patients were analyzed. Mucin and LL-37 were both measured at high concentrations in samples of patients with cystic fibrosis. The most important finding of the present study is that the AMP LL-37 binds to mucins and that this interaction inhibits the antimicrobial activity of the peptide. A number of pulmonary diseases, as chronic obstructive pulmonary disease (COPD) or cystic fibrosis, for example, are characterized by increased amounts of airway mucus and decreased host defense leading to more susceptibility to pulmonary infections. It is possible that the mechanism described in the present study contributes to the less effective host defense in theese deseases.