Lactoferrin (LF), also known as lactotransferrin (LTF), is a multifunctional protein of the transferrin family. Lactoferrin is a globular glycoprotein with a molecular mass of about 80 kDa that is widely represented in various secretory fluids, such as milk, saliva, tears, and nasal secretions. Lactoferrin is also present in secondary granules of PMN and is secreted by some acinar cells. Lactoferrin can be purified from milk or produced recombinantly. Human colostrum ("first milk") has the highest concentration, followed by human milk, then cow milk (150 mg/L).[1]

Lactoferrin is one of the components of the immune system of the body; it has antimicrobial activity (bacteriocide, fungicide) and is part of the innate defense, mainly at mucoses.[1] In particular, lactoferrin provides antibacterial activity to human infants.[2][3] Lactoferrin interacts with DNA and RNA, polysaccharides and heparin, and shows some of its biological functions in complexes with these ligands.

Biological functions

Lactoferrin belongs to the innate immune system. Apart from its main biological function, namely binding and transport of iron ions, lactoferrin also has antibacterial, antiviral, antiparasitic, catalytic, anti-cancer, anti-allergic and radioprotecting functions and properties.[21]

Antibacterial activity

Antibacterial activity of lactoferrin is best studied; it originates from the iron-binding properties of lactoferrin, which deprive the bacterial flora from an element necessary for its growth.[22] Antibacterial action of lactoferrin is also explained by the presence of specific receptors on the cell surface of microorganisms. Lactoferrin binds to lipopolysaccharide of bacterial walls, and the oxidized iron part of the lactoferrin oxidizes bacteria via formation of peroxides. This affects the membrane permeability and results in the cell breakdown (lysis).[22]

Although lactoferrin also has other antibacterial mechanisms not related to iron, such as stimulation of phagocytosis,[23] the interaction with the outer bacterial membrane described above is the most dominant and most studied.[24] Lactoferrin not only disrupts the membrane, but even penetrates into the cell. Its binding to the bacteria wall is associated with the specific peptide lactoferricin, which is located at the N-lobe of lactoferrin and is produced by in vitro cleavage of lactoferrin with another protein, trypsin.[25][26]

Antiviral activity

Lactoferrin acts, mostly in vitro, on a wide range of human and animal viruses based on DNA and RNA genomes,[27] including the herpes simplex virus 1 and 2,[28][29] cytomegalovirus,[30] HIV,[29][31] hepatitis C virus,[32][33] hantaviruses, rotaviruses, poliovirus type 1,[34] human respiratory syncytial virus and murine leukemia viruses.[26]

The most studied mechanism of antiviral activity of lactoferrin is its diversion of virus particles from the target cells. Many viruses tend to bind to the lipoproteins of the cell membranes and then penetrate into the cell.[33] Lactoferrin binds to the same lipoproteins thereby repelling the virus particles. Iron-free apolactoferrin is more efficient in this function than hololactoferrin; and lactoferricin, which is responsible for antimicrobial properties of lactoferrin, shows almost no antiviral activity.[27]

Beside interacting with the cell walls, lactoferrin also directly binds to viral particles, such as the hepatitis viruses.[33] This mechanism is also confirmed by the antiviral activity of lactoferrin against rotaviruses,[26] which act on different cell types.

Lactoferrin also suppresses virus replication after the virus penetrated into the cell.[26][31] Such an indirect antiviral effect is achieved by affecting natural killer cells, granulocytes and macrophages – cells, which play a crucial role in the early stages of viral infections, such as severe acute respiratory syndrome (SARS).[35]

Antifungal activity

Lactoferrin and lactoferricin inhibit in vitro growth of Trichophyton mentagrophytes, which are responsible for several skin diseases such as ringworm.[36] Lactoferrin also acts against the Candida albicans – a diploid fungus (a form of yeast) that causes opportunistic oral and genital infections in humans.[37][38] Fluconazole has long been used against Candida albicans, which resulted in emergence of strains resistant to this drug. However, a combination of lactoferrin with fluconazole can act against fluconazole-resistant strains of Candida albicans as well as other types of Candida: C. glabrata, C. krusei, C. parapsilosis and C. tropicalis.[37] Antifungal activity is observed for sequential incubation of Candida with lactoferrin and then with fluconazole, but not vice versa. The antifungal activity of lactoferricin exceeds that of lactoferrin. In particular, synthetic peptide 1-11 lactoferricin shows much greater activity against Candida albicans than native lactoferricin.[37]

Administration of lactoferrin through drinking water to mice with weakened immune systems and symptoms of aphthous ulcer reduced the number of Candida albicans strains in the mouth and the size of the damaged areas in the tongue.[39] Oral administration of lactoferrin to animals also reduced the number of pathogenic organisms in the tissues close to the gastrointestinal tract. Candida albicans could also be completely eradicated with a mixture containing lactoferrin, lysozyme and introakonazol in HIV-positive patients who were resistant to other antifungal drugs.[40] Such antifungal action when other drugs deem inefficient is characteristic of lactoferrin and is especially valuable for HIV-infected patients.[41] Contrary to the antiviral and antibacterial actions of lactoferrin, very little is known about the mechanism of its antifungal action. Lactoferrin seem to destroy the cell wall and binds the plasma membrane of C. albicans.[38]

Interaction with nucleic acids

One of the important properties of lactoferrin is its ability to bind with nucleic acids. The fraction of protein extracted from milk, contains 3.3% RNA,[17] besides, the protein preferably binds to the double-stranded then to the single-stranded DNA. The ability of lactoferrin to bind DNA is used for the isolation and purification of lactoferrin using affinity chromatography with columns containing immobilized DNA-containing sorbents, such as agarose with the immobilized single-stranded DNA.[42]

Enzymatic activity of lactoferrin

Lactoferrin hydrolyzes RNA and exhibits the properties of pyrimidine-specific secretory ribonucleases. In particular, by destroying the RNA genome, milk RNase inhibits reverse transcription of retroviruses that cause breast cancer in mice.[43] Parsi women in West India have the milk RNase level markedly lower than in other groups, and their breast cancer rate is three times higher than average.[44] Thus, ribonucleases of milk, and lactoferrin in particular, might play an important role in pathogenesis of diseases caused by various retroviruses.

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