Abstract
Due to the emergence of multidrug-resistant pathogens, it is necessary to develop options to fight infections caused by these agents. Lactoferrin (Lf) is a cationic nonheme multifunctional glycoprotein of the innate immune system of mammals that provides numerous benefits. Lf is bacteriostatic and/or bactericidal, can stimulate cell proliferation and differentiation, facilitate iron absorption, improve neural development and cognition, promote bone growth, prevent cancer and exert anti-inflammatory and immunoregulatory effects. Lactoferrin is present in colostrum and milk and is also produced by the secondary granules of polymorphonuclear leukocytes, which store this glycoprotein and release it at sites of infection. Lf is also present in many fluids and exocrine secretions, on the surfaces of the digestive, respiratory and reproductive systems that are commonly exposed to pathogens. Apo-Lf (an iron-free molecule) can be microbiostatic due to its ability to capture ferric iron, blocking the availability of host iron to pathogens. However, apo-Lf is mostly microbicidal via its interaction with the microbial surface, causing membrane damage and altering its permeability function. Lf can inhibit viral entry by binding to cell receptors or viral particles. Lf is also able to counter different important mechanisms evolved by microbial pathogens to infect and invade the host, such as adherence, colonization, invasion, production of biofilms and production of virulence factors such as proteases and toxins. Lf can also cause mitochondrial and caspase-dependent regulated cell death and apoptosis-like in pathogenic yeasts. All of these mechanisms are important targets for treatment with Lf. Holo-Lf (the iron-saturated molecule) can contain up to two ferric ions and can also be microbicidal against some pathogens. On the other hand, lactoferricins (Lfcins) are peptides derived from the N-terminus of Lf that are produced by proteolysis with pepsin under acidic conditions, and they cause similar effects on pathogens to those caused by the parental Lf. Synthetic analog peptides comprising the N-terminus Lf region similarly exhibit potent antimicrobial properties. Importantly, there are no reported pathogens that are resistant to Lf and Lfcins; in addition, Lf and Lfcins have shown a synergistic effect with antimicrobial and antiviral drugs. Due to the Lf properties being microbiostatic, microbicidal, anti-inflammatory and an immune modulator, it represents an excellent natural alternative either alone or as adjuvant in the combat to antibiotic multidrug-resistant bacteria and other pathogens. This review aimed to evaluate the data that appeared in the literature about the effects of Lf and its derived peptides on pathogenic bacteria, protozoa, fungi and viruses and how Lf and Lfcins inhibit the mechanisms developed by these pathogens to cause disease.
Highlights
Except for some bacterial species, all life forms require iron to survive
As with other pathogens, when researchers design a drug with effects against parasites, they hope that the drug acts exclusively on the parasite; to ensure this, the selected target is usually a biological process or a molecule that is only expressed in the specific pathogen and not in the host
In a study where the effect of bovine Lf (bLf) on this parasite was elegantly demonstrated, Frontera et al determined by fluorescence microscopy that apo-bLf and synthetic bLfcin at sublethal concentrations showed binding to the surface of G. lamblia, and after a few minutes, these molecules were observed in the cell interior
Summary
Except for some bacterial species, all life forms require iron to survive. This transition metal is toxic and has low solubility; it is usually bound to proteins. Iron homeostasis carried out by regulatory systems is necessary due to the reactive oxygen species (ROS) produced by the Fenton reaction, which damage lipids, proteins and DNA. In addition to iron being an essential nutrient, the iron concentration inside the body must be perfectly regulated Since both the host and pathogenic invading microorganisms require iron for growth, a battle begins between the host and pathogens when pathogens enter the body and attempt to obtain iron for colonization and as a display of their virulence factors. Lf is normally 15% iron-saturated in humans; Lf could have higher iron saturation, depending on the diet and overall levels in some diseases If this is the case, the resulting holo-Lf can be an iron source for specific pathogens for growth and colonization [13]; for a few pathogens, holo-Lf can be microbicidal. The objective of this review was to evaluate the data that appeared in the literature about the effects of Lf and its derived peptides on pathogenic bacteria, protozoa, fungi and viruses and the ways in which Lf and Lfcins inhibit the mechanisms developed by these pathogens to cause disease
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