Drosomycin-Like Defensin, a Human Homologue ofDrosophila melanogasterDrosomycin with Antifungal Activity

Abstract

Innate antifungal defense in Drosophila melanogaster relies on the activation of the Toll molecule and the release of drosomycin, a defensin-like molecule with antifungal properties. Ten human homologues of Toll have been described, with central roles in activation of the innate host defense. In the present study, we report a putative human homologue of the Drosophila-derived drosomycin, designated drosomycin-like defensin (DLD). Synthetic DLD displays a broad spectrum of activity against Aspergillus spp. and other clinically relevant filamentous fungi. These effects are specific for filamentous fungi; no activity has been found against yeasts or gram-positive or gram-negative bacteria. Synthetic DLD also displays immunomodulatory effects on Aspergillus-stimulated cytokine production. In addition, we show the expression of DLD mRNA in several human tissues, particularly in the skin, consistent with its putative role as a defensin against invading microorganisms. This is the first indication of an endogenous human peptide with specific antifungal activity, which is probably central in the defense against infections with molds.Drosophila melanogaster, like other insects, relies on both cellular and humoral mechanisms to mount its antimicrobial host defense. The mainstay of its humoral defense is the injuryinduced secretion of an array of antimicrobial peptides by the fat body, the functional equivalent of the liver (9, 10). To date, seven distinct families of antimicrobial peptides from immunechallenged Drosophila flies have been characterized, each with a specific spectrum of activity. Among these peptides, drosomycin is highly active against filamentous fungi, protecting Drosophila from infections by Aspergillus fumigatus, whereas no activity against gram-positive or gram-negative bacteria has been found (9). The release of drosomycin is under the control of signals mediated by Toll, a transmembrane receptor activated by a cytokine-like protein, Spaetzle (16).Comparison of the Toll complex with that of mammalian innate defense mechanisms has revealed that the intracellular tail of Toll shows a striking homology with the intracellular domain of interleukin-1 receptor type I (IL-1RI), later designated the Toll/IL-1R (TIR) domain (23). Moreover, the intracellular signaling pathway induced by Drosophila Toll is highly similar to the intracellular pathways activated by IL-1RI (12). Eleven different Toll-like receptors (TLRs) have been identified in mammals and have been demonstrated to be crucial for the recognition of pathogenic microorganisms and the activation of the innate immune response in general (24), including antifungal defense (2, 20, 21). Where Toll activation leads to the direct release of drosomycin, engagement of TLRs induces the release of cytokines and ␣-and ␤-defensins (4, 6), but to date no human homologue of drosomycin has been reported.In the present study, we report a putative human peptide with high homology with drosomycin, and we demonstrate potent antifungal properties for this peptide, desi...

Establishing a reference array for the CS-αβ superfamily of defensive peptides

“…Consistent with this hypothesis, both charybdotoxin and defensin from Leiurus have short n-loops, but charybdotoxin has the sequence “GKCMN” while the defensin has “GYCAG.” Charybdotoxin also has antimicrobial activity, so while the short n-loop and KCXN motif may be sufficient to indicate toxic activity, the characteristics suggesting antimicrobial activity are less clear. Drosomycin-like defensin (DLD) from humans has activity specifically against filamentous fungi, despite the sequence not having conventional CSH, CS-αβ, or γ-core motifs [80]. …”

Drosophila melanogaster as a model host to dissect the immunopathogenesis of zygomycosis

“…By studying the comparative kinetics of mRNA induction of the two major antifungal peptides, Drs and Mtk, which are under the control of the Tl pathway, we found that the Tl pathway was rapidly and efficiently activated by Zygomycetes and A. fumigatus to a comparable degree. Nonetheless, we cannot exclude selective degradation of antifungal peptides in D. melanogaster by Zygomycetes toxins (40), or that Zygomycetes spores might be less susceptible to the effects of D. melanogaster antifungal peptides than A. fumigatus spores (41).…”

Host-defense peptides of the skin with therapeutic potential: From hagfish to human

“…Interleukin-37 (IL-37) is considered to be a fundamental inhibitor of innate immunity decreasing the production of pro-inflammatory cytokines and so protecting against inflammatory and autoimmune diseases. hBD-3, but not hBD-1, -2, and -4, up-regulates the mRNA and protein expression of IL-37 in human keratinocytes and stimulates the release of IL-37 into culture supernatants [98]. IL-37 is highly expressed in psoriatic skin and so hBD-3 may have a role in therapy for cutaneous inflammatory diseases through regulation of IL-37 expression.…”

“…[113]). These include the cathelicidinrelated peptide LL-37 [44], the ␤-defensins hBD-1 [8], hBD-2 [6], and hBD-3 [53], chimerin [2,109], several chemokines such as CCL20/MIP-3␣ [129], dermcidin [93], drosomycin-like defensin (DLD) [98], psoriasin (S100A7) [48] and the structurally similar koebnerisin (S100A15) [119], and RNase 7 [54]. In addition, neuronal/neuroendocrine peptides such as substance P, CGRP, ␣-MSH, NPY, TRH, and VIP present in the skin show varying degrees of antibacterial activity [5].…”