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

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

Effect of lactoferrin feeding on the host antifungal response in guinea-pigs infected or immunised with Trichophyton mentagrophytes

“…It is known that LF or its peptide fragment(s) stimulate phagocytic activity [23] and superoxide production [24] of neutrophil PMNLs in vitro. Recently, it was reported that intravenous injection of LF peptide upregulates neutrophil PMNL functions, including superoxide generation, in Candida albicans-infected mice [25]. Such effects of LF may not be exerted by orally administered LF, because substantial amounts of LF or LF fragments cannot be absorbed from the intestinal lumen, as shown previously [26].…”

Iron Chelation Via Deferoxamine Exacerbates Experimental Salmonellosis Via Inhibition of the Nicotinamide Adenine Dinucleotide Phosphate Oxidase-Dependent Respiratory Burst

“…Thus, two different Fe-binding molecules had opposite effects on the outcome of infection with S. typhimurium. Recently, the antimicrobial activity of LF has been ascribed to the action of a peptide contained within the bovine LF molecule (20). However, both in vivo and in vitro, this peptide had no effect on the growth of Salmonella (data not shown), and LF has no direct influence on S. typhimurium growth in broth culture.…”

The Early Transcriptional Response of Human Granulocytes to Infection withCandida albicansIs Not Essential for Killing but Reflects Cellular Communications

“…Components potentially involved in killing include lactoferrin, which is secreted in the PMN fractions. Several previous studies have demonstrated the candidacidal properties of lactoferrin (29,39,41). The only gene representing the neutrophil granule proteins, which was significantly upregulated, was the protease urokinase-type plasminogen activator (i.e., PLAU) (13).…”