Lactoferrin peptide increases the survival of Candida albicans-inoculated mice by upregulating neutrophil and macrophage functions, especially in combination with amphotericin B and granulocyte-macrophage colony-stimulating factor.
To develop a new strategy to control candidiasis, we examined in vivo the anticandidal effects of a synthetic lactoferrin peptide, FKCRRWQWRM (peptide 2) and the peptide that mimics it, FKARRWQWRM (peptide 2'). Although all mice that underwent intraperitoneal injection of 5 x 10(8) Candida cells with or without peptide 2' died within 8 or 7 days, respectively, the survival times of mice treated with 5 to 100 microg of intravenous peptide 2 per day for 5 days after the candidal inoculation were prolonged between 8.4 +/- 2.9 and 22.4 +/- 3.6 days, depending on the dose of peptide 2. The prolongation of survival by peptide 2 was also observed in mice that were infected with 1.0 x 10(9) Candida albicans cells (3.2 +/- 1.3 days in control mice versus 8.2 +/- 2.4 days in the mice injected with 10 microg of peptide 2 per day). In the high-dose inoculation, a combination of peptide 2 (10 microg/day) with amphotericin B (0.1 microg/day) and granulocyte-macrophage colony-stimulating factor (GM-CSF) (0.1 microg/day) brought prolonged survival. With a combination of these agents, 60% of the mice were alive for more than 22 days. Correspondingly, peptide 2 activated phagocytes inducing inducible NO synthase and the expression of p47(phox) and p67(phox), and peptide 2 increased phagocyte Candida-killing activities up to 1.5-fold of the control levels upregulating the generation of superoxide, lactoferrin, and defensin from neutrophils and macrophages. These findings indicated that the anticandidal effects of peptide 2 depend not only on the direct Candida cell growth-inhibitory activity, but also on the phagocytes' upregulatory activity, and that combinations of peptide 2 with GM-CSF and antifungal drugs will help in the development of new strategies for control of candidiasis.
Tanida
T
T
Department of Oral Surgery, Kochi Medical School, Kohasu, Nankoku-city, Kochi 783-8505, Japan.
Rao
F
F
Hamada
T
T
Ueta
E
E
Osaki
T
T
D000666:Amphotericin B / Q000627:therapeutic use*; D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D002176:Candida albicans / Q000187:drug effects* / Q000254:growth & development; D002177:Candidiasis / Q000382:microbiology; D004359:Drug Therapy, Combination; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D007781:Lactoferrin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D015854:Up-Regulation
D000935:Antifungal Agents; D010455:Peptides; D000666:Amphotericin B; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007781:Lactoferrin