*4.1. Expression*

The most notable AMP exhibiting antiviral activity of the transferrin family of iron-binding proteins is lactoferrin (LF), a multifunctional 80 KDa glycoprotein [71,72]. Originally discovered in bovine milk, LF is highly conserved and can be found in humans, mice, and porcine species. It is expressed in most biological fluids such as exocrine secretions (milk, saliva, fluids of digestive tract, and tears) and in neutrophil granules [72,73]. LF serves as a key component of innate immune defenses and demonstrates antimicrobial activity against a wide range of bacteria and viruses through direct action on pathogen membrane and target host cell moieties as well as through modulation of inflammation (Table 1) [72,74].

LF expression may be induced under hormonal control by epithelial cells in mammary glands or at well-defined stages of cell cycle such as neutrophil differentiation [74,75]. LF structure consists of a polypeptide chain that is characterized by a highly basic and positively-charged N-terminal region [74,76]. The LF chain folds into two globular lobes linked by a three-turn alpha helix, with each lobe containing an iron-binding site [77]. There is a strong interaction between the two lobes when iron is bound, which renders LF resistant to proteolysis in this holo form as compared to an open apo form [77]. In the stomach, acidic pepsin hydrolysis of the N-terminal of LF yields lactoferricin (Lfcin), a 25-amino-acid peptide with multiple hydrophobic, positively-charged residues [74,76]. Lfcin retains the properties of LF and demonstrates potent antiviral activity.

#### *4.2. Respiratory Syncytial Virus*

Early studies have demonstrated the direct anti-RSV activity of LF in vitro [78–80]. In HEp-2 cells, LF (100 μg/mL) decreased the production of IL-8 induced by RSV infection when pre-incubated with virions. This LF-mediated inhibition was dependent on LF–RSV interactions as LF inhibited RSV entry into HEp-2 cells [79]. Pre-incubation of LF (100 μg/mL) with RSV resulted in decreased viral entry. LF was found to inhibit RSV entry by directly binding to the F1 subunit of the RSV F protein, which mediates fusion of the virion with the cell membrane [79].
