Epithelial antimicrobial peptides in host defense against infection

Abstract

One component of host defense at mucosal surfaces seems to be epithelium-derived antimicrobial peptides. Antimicrobial peptides are classified on the basis of their structure and amino acid motifs. Peptides of the defensin, cathelicidin, and histatin classes are found in humans. In the airways, alpha-defensins and the cathelicidin LL-37/hCAP-18 originate from neutrophils. beta-Defensins and LL-37/hCAP-18 are produced by the respiratory epithelium and the alveolar macrophage and secreted into the airway surface fluid. Beside their direct antimicrobial function, antimicrobial peptides have multiple roles as mediators of inflammation with effects on epithelial and inflammatory cells, influencing such diverse processes as proliferation, immune induction, wound healing, cytokine release, chemotaxis, protease-antiprotease balance, and redox homeostasis. Further, antimicrobial peptides qualify as prototypes of innovative drugs that might be used as antibiotics, anti-lipopolysaccharide drugs, or modifiers of inflammation.

Figure 1

Host defense mechanisms of the respiratory epithelium. Coughing and cilia mechanically remove inhaled debris and microorganisms entrapped in mucus, a mechanism called mucociliary clearance. Multiple substances with proinflammatory and anti-inflammatory as well as antimicrobial activities are secreted by epithelial and inflammatory cells and function as effector substances of the innate immune system. Natural killer cells, dendritic cells, neutrophils, and macrophages represent the cellular components of innate immunity. Cells of the respiratory epithelium (1=ciliated cell, 2=goblet cell, 3=basal cell, 4=mucous and serous gland cells) are not passive bystanders of an inflammatory process but secrete effector molecules including antimicrobial peptides. The adaptive immune response with its T cells and B cells (sIgA=secretory immunoglobulin A) is triggered by innate mechanisms.

Figure 2

Classification of antimicrobial peptides based on motifs in the amino acid sequence similar to that described by Boman [63]. Antimicrobial peptides could also be grouped according to other principles. LL-37 and PR-39 belong to the cathelicidin family on the basis of their homologous propeptide. rTD-1=rhesus monkey θ-defensin 1; PR-39=cathelicidin from pig. Human β-defensin 3 (hBD-3) was identified by using bioinformatic screening procedures to search human chromosome 8p23 for the presence of sequence motifs typical of β-defensin (R Bals, unpublished data).

Figure 3

Structure of prototypical genes and peptides of the defensin and cathelicidin families. Both gene types have several exons whose primary translational product is a prepropeptide. The C-terminus is the part of the molecules that contains antimicrobial activity. The genes are represented schematically with the following individual components: 5' untranslated region (5' UTR), white box; signal sequence, shaded box; prosequence, black box; mature peptide, hatched box; 3' UTR, white box.

Figure 4

Activities of antimicrobial peptides. As well as their antimicrobial function (1), antimicrobial peptides have other potential roles in inflammation and infection (2,3). The mechanism of the antimicrobial activity is explained in the insert. After electrostatic interactions between the negatively charged bacterial wall and the positively charged peptides (a), the peptide associates with the membranes, either by insertion as pores (b) or by forming carpet-like structures that lead to a destabilization of the membrane. The sources (1) of antimicrobial peptides in the airways are epithelial cells and inflammatory cells. Defensins and LL-37 have a feedback mediator function that targets these cell types (2,3), influencing the release of mediators and other cellular processes such as proliferation and chemoattraction.