The antimicrobial activity of lactoferrin: current status and perspectives

Lactoferrin (Lf) is a multifunctional iron glycoprotein which is known to exert a broad-spectrum primary defense activity against bacteria, fungi, protozoa and viruses. Its iron sequestering property is at the basis of the bacteriostatic effect, which can be counteracted by bacterial pathogens by two mechanisms: the production of siderophores which bind ferric ion with high affinity and transport it into cells, or the expression of specific receptors capable of removing the iron directly from lactoferrin at the bacterial surface. A particular aspect of the problem of iron supply occurs in bacteria (e.g. Legionella) which behave as intracellular pathogens, multiplying in professional and non professional macrophages of the host. Besides this bacteriostatic action, Lf can show a direct bactericidal activity due to its binding to the lipid A part of bacterial LPS, with an associated increase in membrane permeability. This action is due to lactoferricin (Lfc), a peptide obtained from Lf by enzymatic cleavage, which is active not only against bacteria, but even against fungi, protozoa and viruses. Additional antibacterial activities of Lf have also been described. They concern specific effects on the biofilm development, the bacterial adhesion and colonization, the intracellular invasion, the apoptosis of infected cells and the bactericidal activity of PMN. The antifungal activity of Lf and Lfc has been mainly studied towards Candida, with direct action on Candida cell membranes. Even the sensitivity of the genus tricophyton has been studied, indicating a potential usefulness of this molecule. Among protozoa, Toxoplasma gondii is sensitive to Lf, both in vitro and in vivo tests, while Trichomonads can use lactoferrin for iron requirements. As to the antiviral activity, it is exerted against several enveloped and naked viruses, with an inhibition which takes place in the early phases of viral invection, as a consequence of binding to the viral particle or to the cell receptors for virus. The antiviral activity of Lf has also been demonstrated in in vivo model invections and proposed for a selective delivery of antiviral drugs. The new perspectives in the studies on the antimicrobial activity of Lf appear to be linked to its potential prophylactic and therapeutical use in a considerable spectrum of medical conditions, taking advantage of the availability of the recombinant human Lf. But the historical evolution of our knowledge on Lf indicates that its antimicrobial activity must be considered in a general picture of all the biological properties of this multifunctional protein.