Regulation of fungal infection by a combination of amphotericin B and peptide 2, a lactoferrin peptide that activates neutrophils

Clin Diagn Lab Immunol. 2004 Nov;11(6):1111-9. doi: 10.1128/CDLI.11.6.1111-1119.2004.


To establish a novel strategy for the control of fungal infection, we examined the antifungal and neutrophil-activating activities of antimicrobial peptides. The duration of survival of 50% of mice injected with a lethal dose of Candida albicans (5 x 10(8) cells) or Aspergillus fumigatus (1 x 10(8) cells) was prolonged 3 to 5 days by the injection of 10 microg of peptide 2 (a lactoferrin peptide) and 10 microg of alpha-defensin 1 for five consecutive days and was prolonged 5 to 13 days by the injection of 0.1 microg of granulocyte-monocyte colony-stimulating factor (GM-CSF) and 0.5 microg of amphotericin B. When mice received a combined injection of peptide 2 (10 microg/day) with amphotericin B (0.5 microg/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 alpha-defensin 1, beta-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 (O2-) by neutrophils. The upregulation by peptide 2 was confirmed by the activation of the O2- -generating pathway, i.e., activation of large-molecule guanine binding protein, phosphatidyl-inositol 3-kinase, protein kinase C, and p47phox as well as p67phox. 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.

MeSH terms

  • Amphotericin B / administration & dosage*
  • Animals
  • Antifungal Agents / administration & dosage*
  • Aspergillosis / drug therapy*
  • Aspergillosis / metabolism
  • Aspergillosis / pathology
  • Aspergillus fumigatus*
  • Candida albicans*
  • Candidiasis / pathology
  • Cells, Cultured
  • Female
  • Lactoferrin / administration & dosage*
  • Mice
  • Neutrophil Activation / drug effects
  • Peptides / administration & dosage*
  • Signal Transduction / drug effects
  • alpha-Defensins / administration & dosage


  • Antifungal Agents
  • Peptides
  • alpha-Defensins
  • Amphotericin B
  • Lactoferrin