The antibacterial and antifungal properties of trappin‐2 (pre‐elafin) do not depend on its protease inhibitory function

Abstract

Trappin‐2 (also known as pre‐elafin) is an endogenous inhibitor of neutrophil serine proteases and is involved in the control of excess proteolysis, especially in inflammatory events, along with the structurally related secretory leucocyte proteinase inhibitor. Secretory leucocyte proteinase inhibitor has been shown to have antibacterial and antifungal properties, whereas recent data indicate that trappin‐2 has antimicrobial activity against Pseudomonas aeruginosa and Staphylococcus aureus. In the present study, we tested the antibacterial properties of trappin‐2 towards other respiratory pathogens. We found that trappin‐2, at concentrations of 5–20 μm, has significant activity against Klebsiella pneumoniae, Haemophilus influenzae, Streptococcus pneumoniae, Branhamella catarrhalis and the pathogenic fungi Aspergillus fumigatus and Candida albicans, in addition to P. aeruginosa and S. aureus. A similar antimicrobial activity was observed with trappin‐2 A62D/M63L, a trappin‐2 variant that has lost its antiprotease properties, indicating that trappin‐2 exerts its antibacterial effects through mechanisms independent from its intrinsic antiprotease capacity. Furthermore, the antibacterial and antifungal activities of trappin‐2 were sensitive to NaCl and heparin, demonstrating that its mechanism of action is most probably dependent on its cationic nature. This enables trappin‐2 to interact with the membranes of target organisms and disrupt them, as shown by our scanning electron microscopy analyses. Thus, trappin‐2 not only provides an antiprotease shield, but also may play an important role in the innate defense of the human lungs and mucosae against pathogenic microorganisms.

Functional Characterization of Polymorphisms in the Peptidase Inhibitor 3 (Elafin) Gene and Validation of Their Contribution to Risk of Acute Respiratory Distress Syndrome

“…Apart from its well known inhibitory properties, pre-elafin has been found to have broad antimicrobial properties in vitro and in vivo (14,(46)(47)(48). Although the biochemical mechanism responsible for the antimicrobial activities has not yet been elucidated, it is well known that the antimicrobial activities of pre-elafin are independent of their antiproteinase function (47)(48)(49).…”

“…Although the biochemical mechanism responsible for the antimicrobial activities has not yet been elucidated, it is well known that the antimicrobial activities of pre-elafin are independent of their antiproteinase function (47)(48)(49). Recent studies have demonstrated that the N terminus of pre-elafin, responsible for most of the antimicrobial activity of the protein, adopts an a-helical conformation in the presence of a membrane mimetic, which is typical of many antimicrobial peptides (49).…”

Host Defense Peptide Expression in Human Cervical Cells and Regulation by 1,25-Dihydroxyvitamin D3 in the Presence of Cytokines and Bacterial Endotoxin

“…It would be useful in future experiments to assess the functional impact of HVF and ECF with different concentrations of HDPs in terms of using bacterial killing assays. Moreover, there are published studies which demonstrate the antibacterial properties of both elafin and cathelicidn 42,43 .…”

Toll-like receptors as therapeutic targets in cystic fibrosis

“…This effect is mediated via impairment of both AP-1 and NF-κ B activation, via an effect on the ubiquitin-proteasome pathway [136] . Elafin also has antifungal properties [137] . Thus, like SLPI, elafin may hold therapeutic promise in the treatment of inflammation and infection in CF.…”