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

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Abstract
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 × 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 μg 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 × 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 μg of peptide 2 per day). In the high-dose inoculation, a combination of peptide 2 (10 μg/day) with amphotericin B (0.1 μg/day) and granulocyte-macrophage colony-stimulating factor (GM-CSF) (0.1 μg/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.