Expression and Roles of Antimicrobial Peptides in Innate Defense of Airway Mucosa: Potential Implication in Cystic Fibrosis

Abstract

The treatment of respiratory infections is associated with the dissemination of antibiotic resistance in the community and clinical settings. Development of new antibiotics is notoriously costly and slow; therefore, alternative strategies are needed. Antimicrobial peptides (AMPs), the central effector molecules of the immune system, are being considered as alternatives to conventional antibiotics. Most AMPs are epithelium-derived and play a key role in host defense at mucosal surfaces. They are classified on the basis of their structure and amino acid motifs. These peptides display a range of activities, including not only direct antimicrobial activity, but also immunomodulation and wound repair. In the lung, airway epithelial cells and neutrophils, in particular, contribute to AMP synthesis. The relevance of AMPs for host defense against infection has been demonstrated in animal models and is supported by observations in patient studies, showing altered expression and/or unfavorable circumstances for their action in a variety of lung diseases. Of note, AMPs are active against bacterial strains that are resistant to conventional antibiotics, including multidrug-resistant bacteria. Several strategies have been proposed to use these peptides in the treatment of infections, including direct administration of AMPs. In this review, we focus on studies related to direct bactericidal effects of AMPs and their potential clinical applications with a particular focus on cystic fibrosis.

Keywords: antibiotic resistance; antimicrobial effect; antimicrobial peptides; cystic fibrosis; immune modulation; respiratory infections.

Figure 1

Early interactions of cationic antimicrobial peptides with bacterial or host cell membrane. The anionic molecules in the membranes of Gram-negative and Gram-positive bacteria attract cationic AMPs via electrostatic and hydrophobic interactions. In contrast to bacteria, the cytoplasmic membrane of host cells with a neutral net charge connects with cationic AMPs via hydrophobic interactions, which are relatively weak.

Figure 2

Schematic illustration of direct antibacterial mode of actions of antimicrobial peptides.

Figure 3

Schematic illustration of immune-regulatory functions of antimicrobial peptides. AMPs, antimicrobial peptides; IL, interleukin; MCP, monocyte chemoattractant protein; TNF-a, tumor necrosis factor alfa.