Regulation of fungal infection by a combination of amphotericin B and peptide 2, a lactoferrin peptide that activates neutrophils.
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.
Okamoto
Tetsuro
T
Department of Oral Oncology, Kochi Medical School, Kohasu, Oko-cho, Nankoku-city, Kochi 783-8505, Japan.
Tanida
Toyohiro
T
Wei
Benjuan
B
Ueta
Eisaku
E
Yamamoto
Tetsuya
T
Osaki
Tokio
T
D000666:Amphotericin B / Q000008:administration & dosage*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage*; D001228:Aspergillosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001232:Aspergillus fumigatus; D002176:Candida albicans; D002177:Candidiasis / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D007781:Lactoferrin / Q000008:administration & dosage*; D051379:Mice; D018375:Neutrophil Activation / Q000187:drug effects; D010455:Peptides / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D023084:alpha-Defensins / Q000008:administration & dosage
D000935:Antifungal Agents; D010455:Peptides; D023084:alpha-Defensins; D000666:Amphotericin B; D007781:Lactoferrin