A major component of bovine colostrum
by John Buhmeyer, MS
Although first discovered in 1939, the molecule we now know as lactoferrin was not chemically purified and identified until 1960[1]. The term "lacto" in the name refers to the fact that it was originally identified in cow's milk and colostrum. Colostrum is particularly rich in lactoferrin where it makes up approximately 6% of the total protein, but lactoferrin is found in many bodily fluids, including tears, saliva, and other exocrine secretions as well as in neutrophil (white blood cell) granules.
Here it performs a vital function as a major portion of the innate immune system, a non-specific system that forms the initial layer of defense against all forms of pathogens - viral, bacterial, fungal, and even amebic[2]. But lactoferrin has many other functions in the body as well, including participation in iron homeostasis, anti-inflammatory and anti-tumor activity, analgesic activity, regulation of bone metabolism, reproductive functions, and regulation of embryonic development[3].
Lactoferrin's broad spectrum immune function is of primary interest. As part of the innate immune system, it defends against pathogens (disease-causing organisms) of all types. Its antiviral activity is particularly important as there are few pharmaceutical drugs which have proven at all effective against viruses. Lactoferrin has been shown to have antiviral activity against many viruses, including rotavirus (primary cause of diarrhea in young infants)[4], herpes simplex virus 1 and 2[5], canine herpes virus[6], feline herpes virus[7], echovirus[8], enterovirus[9], human papilloma virus (implicated in cervical and other human cancers)[10], polio virus[11], HIV and cytomegalovirus[12], Hepatitis B[13] and C[14] viruses, adenovirus[15], hanta virus[16], influenza virus[17], respiratory syncytial virus[18], Sindbis and Semliki Forest viruses (alphaviruses) [19].
Some of the mechanisms that lactoferrin employs against viruses include:
- Competes with viruses for binding sites on target cells4,5,7,8,9,10
- Binds directly to structural proteins of certain viruses, inactivating them9.
- Interferes with hemagglutination (clumping of red blood cells) caused by influenza viruses17.
Lactoferrin also is very active against other pathogens, such as bacteria, fungi, and amebic parasites[25], while promoting the growth of beneficial bacteria, such as Lactobacilli and Bifidobacteria[26],[27], to pass unharmed into the digestive tract.
- Lactoferrin prevents the colonization of Haemophilus influenzae, a major cause of ear and respiratory infections in children[28].
- Lactoferrin kills dangerous gram-negative bacteria, such as Vibrio cholerae, the cause of cholera, Salmonella, and E. coli[29] by attaching to and destroying the cell wall of the bacterium, allowing lysozyme to enter and lyse, or burst, the cell.
- Lactoferrin is very effective against fungal infections, such as Candida, through its iron-binding ability[30],[31].
Lactoferrin also plays an important role in the immune system as an immunomodulator and growth stimulator.
- Lactoferrin increases the number and activity of T and B lymphocytes and Natural Killer (NK) cells3.
- Lactoferrin modulates the release of a number of cytokines, including both pro- and anti-inflammatory3.
- Lactoferrin can mediate the response to Cytomegalovirus infection by T-lymphocyte augmentation of NK cell activity[34].
- Lactoferrin increases the cell-killing activity of NK cells and killer T-cells[35].
- Lactoferrin increases the activity of human polymorphonuclear leukocytes (white blood cells)[36].
- Lactoferrin is an essential growth factor for lymphocytes[37].
Similarly, lactoferrin has been shown to inhibit the manifestations of autoimmune disease, which involves down-regulation of the immune system.
- Lactoferrin contols the effector phase of the cellular immune response and inhibits the autoimmune response in mice33.
- Lactoferrin lowers positive Coombs test results (a test for autoimmune blood disease) in mice[38].
In summary, lactoferrin is a multifaceted molecule which can significantly affect immune system performance and provide protection against viruses and other pathogens for which there are few if any effective treatments available.
[1]
[2] Ward, PP, Uribe-Luna S, Conneely,
[3] Artym, J. [Antitumor and chemopreventive activity of lactoferrin] Postȩpy Higieny i Medycyny Doświadczalnej 60:352-369 (2006). Lactoferrin participates in iron homeostasis, has immunoregulatory, anti-inflammatory, anti-tumor, and analgesic actions, regulation of bone metabolism, participates in embryonic development, reproductive functions, and others. It provides anti-tumor protection through its immunomodulatory abilities, so it is of particular value in cancer patients with impaired immunity. Lactoferrin increases the number and the activity of T and B cells and NK cells, stimulates the release of a number of cytokines (IL-1, IL-6, IL-8, IL-18, IFN-γ, TNF-α), increases the phagocytic and cytotoxic activity of monocytes and macrophages, accelerates the maturation of T and B cells, and elevates the expression of several types of cellular receptors, including CD4, zeta chain of the CD3 complex, LFA-1, CD11, ICAM-1, and selectin P. In addition, it also exhibits chemopreventive properties, regulates the activity of Phase I and Phase II enzymes which participate in the activation and detoxification of carcinogens, and regulates the composition of the intestinal flora.
[4] Superti, F, Ammendolia, MG, Valenti, P, Seganti, L. Antirotaviral activity of milk proteins: lactoferrin prevents rotavirus infection in the enterocyte-like cell line HT-29. Medical Microbiology and Immunology (
[5] Jenssen, H. Anti-herpes simplex virus activity of lactoferrin/lactoferricin – an example of antiviral activity of antimicrobial protein/peptide. Cellular and Molecular Life Sciences 62(24):3002-3013 (2005). Lactoferrin and a peptide derived from lactoferrin, lactoferricin, block entry of HSV into cells.
[6] Tanaka, T, Nakatani, S, Xuan, X, Kumura, H, Igarashi, I, Shimazaki, K. Antiviral activity of lactoferrin against canine herpes virus. Antiviral Research 60(3):193-199 (2003). Bovine lactoferrin inhibits both the infection and replication of canine herpes virus in vitro.
[7] Beaumont, SL, Maggs, DJ, Clarke, HE. Effects of bovine lactoferrin on in vitro replication of feline herpes virus. Veterinary Ophthalmology 6(3):245-250 (2003). Bovine lactoferrin has a notable inhibitory effect on the in vitro replication of feline herpes virus prior to and during viral adsorption, but not after. It appears that the lactoferrin blocks adsorption to the cell surface and/or penetration of the virus into the cell.
[8] Pietrantoni, A, Ammendolia, MG, Tinari, A, Siciliano, R, Valenti, P, Superti, F. Bovine lactoferrin peptidic fragments involved in inhibition of Echovirus 6 in vitro infection. Antiviral Research 69(2):98-106 (2006). Lactoferrin inhibits Echovirus 6 infection by blocking viral attachment to cell receptors, possibly due to the cluster of positive charges at its N-terminus.
[9] Weng, TY, Chen, LC, Shyu, HW, Chen, SH, Wang, JR, Yu, CK, Lei, HY, Yeh, TM. Lactoferrin inhibits enterovirus 71 infection by binding to VP1 protein and host cells. Antiviral Research 67(1):31-37 (2005). Lactoferrin binds to host cells, preventing enterovirus 71 from attaching to them. It also interferes with the virus by binding to its VP1 protein.
[10] Drobni, P, Naslund, J, Evander, M. Lactoferrin inhibits human papilloma virus binding and uptake in vitro. Antiviral Research 64(1):63-68 (2004). Lactoferrin, particularly bovine lactoferrin, blocks entry of human papilloma virus (HPV) into target cells in vitro. HPV has been implicated in the development of cervical and other cancers.
[11] McCann, KB, Lee, A, Wan, J, Roginski, H,
[12] Harmsen, MC, et al. Antiviral effects of plasma and milk proteins: lactoferrin shows potent activity against both human immunodeficiency virus and human cytomegalovirus replication in vitro. Journal of Infectious Diseases172(2):380-388 (1995). Lactoferrin can protect against infection by HIV and human cytomegalovirus by blocking entrance into the body.
[13] Hara, K, et al. Lactoferrin inhibits hepatitis B virus infection in cultured human hepatocytes. Hepatology Research 24(3):228 (2002). Bovine lactoferrin prevents infection of cultured human liver cells with hepatitis B virus, while transferrin, casein and lactalbumin have no effect.
[14] Ikeda, M, et al. Lactoferrin markedly inhibits hepatitis C virus infection in cultured human hepatocytes. Biochemistry and Biophysics Research Communications 245(2):549-553 (1998). Bovine lactoferrin inhibits the infection of cultured human liver cells by hepatitis C virus while transferrin does not.
[15]
[16] Murphy, ME, Kariwa, H, Mizutani, T, Tanabe, H, Yoshimatsu, K, Arikawa, J, Takashima, I. Characterization of in vitro and in vivo antiviral activity of lactoferrin and ribavirin upon hanta virus. Journal of Veterinary Medicine and Science 63(6):637-645 (2001). Lactoferrin alone or ribavirin alone significantly inhibited hantavirus focus formation in vitro. When combined, the two completely inhibited focus formation. Lactoferrin inhibits adsorption of the virus to cells, and ribavirin inhibits viral protein synthesis.
[17]
[18] van der Strate, BW, et al. Antiviral activities of lactoferrin. Antiviral Research 52(3):225-239 (2001). Lactoferrin is effective against both DNA and RNA viruses, including rotavirus, respiratory syncytial virus, herpes virus and HIV, both by blocking cellular receptors and by directly binding to the viruses.
[19] Waarts, BL, Aneke, OJ, Smit, JM, Kimata, K, Bittman, R, Meijer, DK, Wilschut, J. Antiviral activity of human lactoferrin: inhibition of alpha virus interaction with heparan sulfate. Virology 333(2):284-292 (2005). Lactoferrin inhibits viral infection by alphaviruses (Sindbis and
[20] Ng, TB, Lam, TL, Au, TK, Ye, XY, Wan, CC. Inhibition of human immunodeficiency virus type 1 reverse transcriptase, protease and integrase by bovine milk proteins. Life Science 69(19):2217-2223 (2001). Lactoferrin strongly inhibits HIV-1 reverse transcriptase and slightly inhibited HIV-1 protease and integrase, enzymes which are crucial to the HIV-1 life cycle.
[21] Ohashi, A, Murata, E, Yamamoto, K, Majima, E, Sano, E, Le, QT, Katunuma, N. New functions of lactoferrin and beta-casein in mammalian milk as cysteine protease inhibitors. Biochemistry and Biophysics Research Communications 306(1):98-103 (2003). Lactoferrin inhibits cathepsin L (a cysteine protease inhibitor), an activity which is dependent on the tertiary structure of lactoferrin. A peptide of lactoferrin shows 90% homology with the sequences of a common active site of cystatins.
[22] Viani, RM, Gutteberg, TJ, Lathey, JL, Spector, SA. Lactoferrin inhibits HIV-1 replication in vitro and exhibits synergy when combined with zidovudine. AIDS 13(10):1273-1274 (1999). Lactoferrin in combination with zidovudine is more effective than either alone in inhibiting HIV-1 replication.
[23] van der Strate, BW, De Boer, FM,
[24] Andersen, JH, Jenssen, H, Gutteberg, TJ. Lactoferrin and lactoferricin inhibit Herpes simplex 1 and 2 infection and exhibit synergy when combined with acyclovir. Antiviral Research 58(3):209-215 (2003). When used against HSV-1 and -2, the combination of lactoferrin or its peptide lactoferricin with acyclovir demonstrated good synergy. The effective dosage of both lactoferrin and acyclovir could be reduced 2-7 times.
[25] van Hooijdonk, AC, Kussendrager, KD, Steijns, JM. In vivo antimicrobial and antiviral activity of components in bovine milk and colostrum involved in non-specific defense. British Journal of Nutrition 84(Suppl.1):S127-S134 (2000). Lactoferrin and lactoperoxidase, both present in colostrum in large amounts, provide non-specific defense against a broad spectrum of pathogens, including bacteria and viruses. This is significant both for the protection of commercially important animals as well as humans.
[26] Kim, WS, et al. Lactoferrin-binding proteins in Bifidobacterium bifidum. Biochemistry and Cell Biology 80(1):91-94 (2002). The presence of lactoferrin-binding proteins in bifidobacteria was confirmed in both the membranes and the cytoplasm of the bacteria.
[27] Petschow, BW, et al. Ability of lactoferrin to promote the growth of Bifidobacterium spp. in vitro is independent of receptor binding capacity and iron saturation level. Journal of Medical Microbiology 48(6):541-549 (1999).
[28] Qiu, J, et al. Human milk lactoferrin inactivates two putative colonization factors expressed by Haemophilus influenzae. Proceedings of the National Academy of Sciences USA 95:12641-12646 (1998). Lactoferrin prevents colonization of Haemophilus influenzae, the primary cause of otitis media and other respiratory infections in children, by inactivating two colonization factors expressed by the bacteria.
[29] Ellison, RT III, Giehl, TJ. Killing of gram-negative bacteria by lactoferrin and lysozyme. Journal of Clinical Investigation 88(4):1080-1091 (1991). Lactoferrin and lysozyme act together to kill gram-negative bacteria, such as Vibrio cholerae (cholera), Salmonella typhimurium (food poisoning) and Eschericia coli. The lactoferrin attaches to and destroys the cell wall of the bacteria, allowing the lysozyme to enter and lyse (burst) the organisms.
[30] Andersson, Y, et al. Lactoferrin is responsible for the fungistatic effect of human milk. Early Human Development 59:95-105 (2000). Lactoferrin, through its iron-binding ability, is very effective against fungal infections with Candida and other fungi.
[31] Samaranayake, YH, et al. Antifungal effects of lysozyme and lactoferrin against genetically similar, sequential Candida albicans isolates from a human immunodeficiency virus-infected Southern Chinese cohort. Journal of Clinical Microbiology 39(9):3296-3302 (2001). Lactoferrin plus lysozyme is very effective in killing nearly all oral strains of Candida, which is of particular importance to AIDS sufferers who are often unable to fight off Candida overgrowths, such as thrush.
[32] Zimecki, M, et al. Human lactoferrin induces phenotypic and functional changes in murine splenic B cells. Immunology 86(1):122-7 (1995). Lactoferrin acts as a maturation factor for B cells with regard to their phenotype and function.
[33] Adamik, B, Wlaszczyk, A. [Lactoferrin - its role in defense against infection and immunotropic properties] Postȩpy Higieny i Medycyny Doświadczalnej 50(1):33-41 (1996). Lactoferrin (LF) is an iron-binding protein found in milk and other secretory fluids of mammals as well as in secondary granules of neutrophils. Receptors for LF were detected and isolated on activated T and B cells, monocytes, intestinal brush border cells, platelets and neoplastic cells. Very low physiologic serum levels of LF increase significantly upon infection. Serum concentration of LF is also elevated in rheumatoid patients. It is suggested that the ability of LF to bind an excess of Fe() ions, needed for growth of microorganisms and tumors, represents an important defence mechanism in humans. LF, in addition, may contribute to the protection against pathogens and their metabolites by enhancing phagocytosis, cell adherence and controlling release of proinflammatory cytokines such as IL-1, IL-6 and TNF-alpha. The protein also diminishes the damaging effects of free radical release. LF possesses interesting immunotropic properties with regard to immature T and B cells by promoting phenotypic and functional maturation of these cells. LF also controls the effector phase of cellular immune response and inhibits manifestations of autoimmune response in mice.
[34]
[35] Shau, H., et al. Modulation of natural killer and lymphokine-activated killer cell cytotoxicity by lactoferrin. Journal of Leukocyte Biology 51(4):343-349 (1992). Lactoferrin strongly augments the cytotoxic functions of natural killer (NK) cells and lymphokine-activated killer (LK) cells. Newborn infants have low NK and LK activity so lactoferrin may ‘turn on’ these cells in the infant.
[36] Gahr, M, et al. Influence of lactoferrin on the function of human polymorphonuclear leukocytes and monocytes. Journal of Leukocyte Biology 49(5):427-433 (1991). White blood cells (polymorphonuclear leucocytes) exposed to lactoferrin from bovine colostrum exhibit increased motility and produce more superoxide (a powerful antioxidant).
[37] Hashizume, S, et al. Identification of lactoferrin as an essential growth factor for human lymphocytic cell lines in serum-free medium. Biochimica et Biophysica Acta 763(4):377-382 (1983). Lactoferrin is an essential growth factor for lymphocytes. It has higher growth stimulatory activity than transferrin. Bovine lactoferrin was found to be as effective as human.
[38] Zimecki, M, et al. Lactoferrin lowers the incidence of positive Coombs' test in