Lung antimicrobial proteins and peptides: from host defense to therapeutic strategies

Abstract

Representing severe morbidity and mortality globally, respiratory infections associated with chronic respiratory diseases, including complicated pneumonia, asthma, interstitial lung disease, and chronic obstructive pulmonary disease, are a major public health concern. Lung health and the prevention of pulmonary disease rely on the mechanisms of airway surface fluid secretion, mucociliary clearance, and adequate immune response to eradicate inhaled pathogens and particulate matter from the environment. The antimicrobial proteins and peptides contribute to maintaining an antimicrobial milieu in human lungs to eliminate pathogens and prevent them from causing pulmonary diseases. The predominant antimicrobial molecules of the lung environment include human α- and β-defensins and cathelicidins, among numerous other host defense molecules with antimicrobial and antibiofilm activity such as PLUNC (palate, lung, and nasal epithelium clone) family proteins, elafin, collectins, lactoferrin, lysozymes, mucins, secretory leukocyte proteinase inhibitor, surfactant proteins SP-A and SP-D, and RNases. It has been demonstrated that changes in antimicrobial molecule expression levels are associated with regulating inflammation, potentiating exacerbations, pathological changes, and modifications in chronic lung disease severity. Antimicrobial molecules also display roles in both anticancer and tumorigenic effects. Lung antimicrobial proteins and peptides are promising alternative therapeutics for treating and preventing multidrug-resistant bacterial infections and anticancer therapies.

Keywords: antibiotic resistance; antimicrobial peptide (AMP); antimicrobial proteins and peptides (AMPPs); immunomodulation; lung cancer; pneumonia.

Graphical abstract

FIGURE 1.

Principal features of antimicrobial peptides (AMPs): expression, structural features, and production sites. TLR, toll-like receptor.

FIGURE 2.

Antimicrobial proteins and peptides of the upper and lower airways. Antimicrobial molecules are critical mediators of first-line defense against pathogens, modulate the immune response, and regulate inflammation associated with respiratory disease. AMP, antimicrobial peptide; HBDs, human β-defensins; HNPs, human neutrophil peptides, Lf, lactoferrin; Lz, lysozyme; PLUNC, palate, lung, and nasal epithelium clone; PNEC, pulmonary neuroendocrine cell; SLPI, secretory leukocyte proteinase inhibitor; SP-A/D, surfactant proteins A/D.

FIGURE 3.

Antimicrobial proteins and peptides of the alveoli. AMP, antimicrobial peptide; SP-A/D, surfactant proteins A/D.

FIGURE 4.

Schematic representation of the mode of action of membranolytic antimicrobial peptides (AMPs). A: self-promoted uptake to allow AMP translocation through the LPS-outer membrane in Gram-negative bacteria. B: different models of cytoplasmic membrane perturbation and pore formation (left), compared to the mechanism of AMPs, which inhibit different intracellular biosynthetic processes once they enter the bacterial cytosol.

FIGURE 5.

Antibiofilm activity of antimicrobial peptides (AMPs). AMPs prevent the formation of or destroy produced biofilm through suppression of alarmones, alteration of quorum-sensing communication systems, downregulation of biofilm formation-associated genes, and membrane perturbation of biofilm cells (127). EPS, extracellular polymeric substance; (p)ppGpp, guanosine tetra and pentaphosphate.

FIGURE 6.

Schematic representation of the principal mechanism of antiviral activity of antimicrobial peptides (AMPs).

FIGURE 7.

Schematic representation of immunomodulatory properties of antimicrobial peptides (AMPs).

FIGURE 8.

The innate defense mechanisms of the human lung. The airway surface liquid is comprised of the mucus and periciliary layers, which contain mucins and ciliated epithelial cells that allow for the self-clearance of foreign agents. The secretion of antimicrobial molecules is the first line of defense against respiratory pathogens. AMPPs, antimicrobial proteins and peptides.

FIGURE 9.

Physiology of chronic respiratory diseases. AMP, antimicrobial peptide; ASL, airway surface liquid; CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; COPD, chronic obstructive pulmonary disease.

FIGURE 10.

Antimicrobial activity associated with lung cancers. HBDs, human β-defensins; NSCLC, non-small cell lung cancer; SLPI, secretory leukocyte proteinase inhibitor; SPLUNC1, short-palate, lung, and nasal epithelium clone; SP-A, surfactant protein A.