Regulation of Fungal Infection by a Combination of Amphotericin B and Peptide 2, a Lactoferrin Peptide That Activates Neutrophils

Abstract

To establish a novel strategy for the control of fungal infection, we examined the antifungal and neutrophilactivating activities of antimicrobial peptides. The duration of survival of 50% of mice injected with a lethal dose of Candida albicans (5 ؋ 10 8 cells) or Aspergillus fumigatus (1 ؋ 10 8 cells) was prolonged 3 to 5 days by the injection of 10 g of peptide 2 (a lactoferrin peptide) and 10 g of ␣-defensin 1 for five consecutive days and was prolonged 5 to 13 days by the injection of 0.1 g of granulocyte-monocyte colony-stimulating factor (GM-CSF) and 0.5 g of amphotericin B. When mice received a combined injection of peptide 2 (10 g/day) with amphotericin B (0.5 g/day) for 5 days after the lethal fungal inoculation, their survival was greatly prolonged and some mice continued to live for more than 5 weeks, although the effective doses of peptide 2 for 50 and 100% suppression of Candida or Aspergillus colony formation were about one-third and one-half those of amphotericin B, respectively. In vitro, peptide 2 as well as GM-CSF increased the Candida and Aspergillus killing activities of neutrophils, but peptides such as ␣-defensin 1, ␤-defensin 2, and histatin 5 did not upregulate the killing activity. GM-CSF together with peptide 2 but not other peptides enhanced the production of superoxide (O 2 ؊ ) by neutrophils. The upregulation by peptide 2 was confirmed by the activation of the O 2 ؊ -generating pathway, i.e., activation of large-molecule guanine binding protein, phosphatidyl-inositol 3-kinase, protein kinase C, and p47 phox as well as p67 phox . In conclusion, different from natural antimicrobial peptides, peptide 2 has a potent neutrophil-activating effect which could be advantageous for its clinical use in combination with antifungal drugs.

Immunomodulatory peptides obtained by the enzymatic hydrolysis of whey proteins

“…Peptide 2, consisting of the N-terminal from 17-to -26 amino acids of bLF, has stronger anti-candidal activity than the full-length peptide . This peptide also prolongs the survival of mice infected with a lethal dose of Candida albicans (Tanida, Rao, Hamada, Ueta, & Osaki, 2001), probably by increasing the Candida-killing activities of neutrophils (Okamoto et al, 2004).…”

Fungicidal activity of human lactoferrin-derived peptides based on the antimicrobial αβ region

“…In general, the antifungal mechanism of antimicrobial peptides appears to involve rupture of the fungal membrane and suppression of mitochondrial respiration [3,20].…”

Aspergillus fumigatus and Related Species

“…Cite this article as Cold Spring Harb Perspect Med 2015;5:a019786 the most active factors are the surfactant proteins SPA and SPD, the pentraxin-3-ficolin complexes, and the b-defensins (Okamoto et al 2004;Alekseeva et al 2009;Madan et al 2010;Ma et al 2013). After A. fumigatus conidia bypass mucocilliary clearance and epithelial defenses, they reach the lower airways (Cohen et al 2011).…”