About Lactoferrin and Transferrin - Review | Ora Mune
Inhibitory Effects on Bacterial Growth and BIOFILM Formation.
Lactoferrin is a glycoprotein and a member of transferrin family capable of binding and transferring iron (Fe3+ ions). It is therefore an iron chelator. Lactoferrin is found in small quantities in milk whey and the exocrine secretions of mammals. It is released from neutrophil granules during inflammation and is the main source of lactoferrin in blood plasma. lactoferrin is considered a multifunctional or multi-tasking protein that influences the immune system at the cellular (lymphocytes, phagocytes, neutrophils, natural killer cells) and molecular (cytokines, interleukins, tumor necrosis factor, granulocyte-monocyte stimulating factor) levels. It plays several biological roles and has antibacterial, antiviral, anti fungal, anti-inflammatory, antioxidant and immunomodulatory activities. It affects growth and proliferation of a variety of infectious agents both Gram- positive (Streptococcus pyogenese, Staphylococcus aureus, Listeria monocytogenese) and Gram negative (E. coli, Pseudomonas aeruginosa, Yersinia enterocolica) and other bacteria. It is of interest that while lactoferrin inhibits growth of iron-dependant bacteria, in certain cases in contrast it may serve as an iron donor, and in this manner support the growth of some beneficial bacteria with low iron demands such as Lactobacillus and Bifidobacterium species. The bacterial growth inhibitory activity of lactoferrin due to its iron binding properties makes it of grate importance in SUPPRETION OF BACTERIAL BIOFILM FORMATION discussed bellow.
Transferrin like lactoferrin is an iron binding glycoprotein that constitutes 7.5 to 8% of bovine immunoglobulin (see review bovine immunoglobulin). Similar to lactoferrin, it inhibits multiplication and growth of certain viral, bacterial and fungal organisms by iron inhibition. This property of transferrin has been known for a long time and was shown by this writer in 1968 to inhibit mycobacterial growth as part of his Ph.D. dissertation and by subsequent publications.
Antimicrobial factors constitute one arm of the innate immune system which protect mucosal surfaces from bacterial infections. These factors can rapidly kill bacteria and micro organisms deposited on mucosal surfaces and prevent acute, invasive infections. In many chronic infections, however, bacteria live in complex structures called biofilms. Biofilms are collections of microbial communities encased by a matrix of negatively charged polysaccharides held together by positively charged calcium, magnesium and ironic ions. Within the biofilm the bacteria are protected from immune attack, antibiotics, UV radiation, dehydration, toxic metals and salinity. Further, the matrix allows for free intracellular interactions, exchange of genetic materials, necessary metabolites and nutrients. Given these facts, it is therefore clear that, disruption of biofilm formation from free living independent organisms is of paramount importance in controlling infections. Ample evidence exists that iron binding components of the innate immune system, namely lactoferrin and transferrin (see reviews) fulfill this function. Lactoferrin stimulates twitching, a specialized form of surface motility, causing the bacteria to wander across the surface instead of forming cell clusters and biofilms. Other chelators such as ethylenediaminetetraacetic acid (EDTA) induce dispersal and killing of certain biofilms such as Staph and Pseudomonas species such as P.aeruginosa an exceptionally vicious and devastating infection. The combination of EDTA and antibiotics are effective biofilm disrupters. Immunoglobulins (see reviw immunoglobulins), probiotics (see review probiotics and prebiotics-inulin ) and enzymes are other adjunctive therapies that help fight infections and biofilm formation.
- Manners DJ, Mason AJ, Patterson JC. The structure of a beta-(1-3)-glucan from yeast cell walls. Biochem. J. 135: 19-30, 1973.
- Williams DL, Sherwood ER, Browder JW, etal. Pre clinical safety evaluation of soluble glucan. Int. J. Immunopharmacol. 10: 405-411, 1988.
- DI Luzio NR. Pharmacology of the reticuloendothelial system: accent on glucan. In The Reticuloendothelial System in Health and Disease. Reichard S, Escobar M, and Friedman H, eds. New York, Plenum Press, pp 412-421, 1976.
- Wooles WR, DI Luzio NR, The phagocytic and proliferative response of reticuloendothelial system following glucan administration. J. Reticuloendothelial Sec. 1: 160, 1964.
- Czop LK, Kay j. Isolation and characterization of beta glucan receptors on human mononuclear phagocytes. J. Exp. Med. 173: 1511-1520, 1991.
- Taylor PR, Brown GD, Reid DM, Willment JA, etal. The beta-glucan receptor, Dectin-1 is predominantly expressed on the surface of cells of the monocyte/ macrophage and neutrophil lineages. J. Immunol. 169: 3876-3882, 2002.
- Brown GD, Taylor PR, Reid DM, Willment JA, etal. Dectin-1 is a major beta-glucan receptor on macrophages. J. Exp. Med. 196: 407-412, 2002.
- Herr J, Marshall AS, Caron E, Edwards AD, etal. Derctin-1 utilizes novel mechanisms for yeast phagocytosis in macrophages. Blood Aug 10 (pub ahead of print).
- Suzuki I, Tanaka H, Kinoshita A, Oikawa S, etal. Effect of orally administered beta-glucan on macrophage function in mice. Int. J. Immunopharmacol. 12:675-678, 1990.
- Kokoshis PL, Williams DL, Cook JA, Di Luzio NR. Increased resistance to Staphylococcus aureus infection and enhaucement in serum lysozyme activity by glucan. Science 24: 1340-1342, 1978.
- Di Luzio NR, Williams DL, McNamee RB, Malshet VG. Comparative evaluation of the tumor inhibitory and antibacterial activity of solubilized and particulate glucan. Recent results cancer res. 75: 165-72, 1980.
- Reynolds JA, Kastello MD, Harrington DG, Crabbs CL. Glucan-induced enhaucement of host resistance to selected infectious diseases. Infect. Immun. 30: 51-57, 1980.
- Williams DL, Sherwood ER, Brewder IW, Mcnamee RB, etal. Effect of glucan on neutrophil dynamics and immune function in Escherichia coli peritonitis. J. Surg. Res. 44: 54-61, 1988.
- Williams DL, Di Luzio NR. Glucan-Induced modification of murine Viral hepatitis. Science 208: 67-69, 1980.
- Bistoni F, Vecchiarelli A, Cenci E, puccetti P, etal. Evidence for macrophage-mediated protection against lethal Candida albicns infection. Infect. Immun. 51: 668-674, 1986.
- Williams DL, Cook JA, Hoffman EO, etal. Protective effect of glucan in experimentally induced candidiasis. J. Reticulocndothelial Soc. 23: 479-490, 1978.
- Di Luzio NR, McNamee R, Browder WI, Williams D. Glucan: Inhibition of tumor growth and enhancement of survival in four syngeneic murine tumor models. Cancel Treat. Rep. 62: 1857-1866, 1978.
- Di Luzio NR, Williams DL, McNamee RB, etal. Comparative tumor inhibitory and anti-bacterial activity of soluble and particulate glucan. Int. J. Cancer. 24: 773-779, 1979.
- Di Luzio NR, McNamee R, Jones E, etal. The employment of glucan and glucan activated macrophages in the enhancement of host resistance to malignancies in experimental animals. In M. D. Fink ed. The Macrophage in Neoplasia, pp. 181-198, Academic Press, New York 1976.
- Mansel PWA, etal. Macrophage-mediated destruction of human malignant cells in vivo. J. Natl. Cancer Inst. 54: 571-580, 1975.
- Stewart CC, etal. Preliminary observations on the effect of glucan in combination with radiation and chemotherapy in four murine tumors. Cancer Treat. Rep. 62: 1867-1872, 1978.
- Di Luzio NR, Cook JA, Cohen C, etal. Enhancement of the inhibitory effect of cyclophosphamide on experimental acute myclogenous leukemia by glucan immunopotentiation and the response of serum lysozyme. In control of Neoplasia by Modulation of the Immune System. Ed. M. Chigiros. New York, Raven press 1978.
- Sveinbjornsson B. Inhibition of extablishemtn and growth of mouse liver metastases after treatment with interferon gamma and bet-1,3-glucan. Hepatology 27: 1241-1248, 1998.
- Gyorgy A. Czop JK. Stimulation of human monocyte beta glucan receptors by glucan particies induces production of UNF alpha and IL-1 beta. J. Immunopharmac. 14:1363-1372, 1992.
- Patcheu MI., Mac Vittie TJ. Stimulation of hemopoiesis and euhanced survival following glucan treatment in sub lethally and lethally irradiated mice. Int J. Immunopharmacol. 7:923-923, 1985
- Patchen MI., D' Alesandro MM, Brook I, etal. Glucan: mechanisms involved in its "radio protective" effect. J. Leukoe Biol. 24:95-105, 1987.
- Patchen MI., MacVittie TJ, Brook I. Glucan-induced hemopoietic and immune stimulation: therapeutic effects in sub lethally and lethally irradiated mice. Methods Find. Exp. Chin, Pharmacol. 8:151-155, 1986.
- Walk M, Danon D. Promotion of wound healing by yeast glucan evaluated on single animals. Med Biol. 63:73-80, 1985.
- Martin CM, Jandl JH. Inhibition of virus multiplication by transferrin in M.J. Seven and L. A. Johnson, Editors. Metal binding in medicine, 335 J.B. Lippincott, Philadelphia, 1960.
- Martin CM, Jandl JH, Findland M. Enhancement of acute bacterial infections in rats and mice by iron and their inhibition by human transferrin . J Infec Disease. 1963; 112: 158-163.
- Youdim S. In vivo and in vitro action of ionic iron and chelating agents on Mycobacterial growth. Ph. D. dissertation 1968
- Youdim S. In vitro effect of iron salts and chelating agents on serum tuberculostasis. Am. Rev. Resp Dis.1969; 99:925.
- Sutcliffe MC, Savage, AM. Transferrin- dependent growth inhibition of yeast-phase Histoplasma capsulatum by human serum and lymph. J.Infec Disease.1980; 142: 209-
- Thomas HL, Biggers CJ, Simonton PR. Bacteriostatic inhibition of Klebsiella pneumoniae by three human transferrins. Annals Human Biol. 1977; 4: 281-284.
- Singh PK, Parsek MR, Greenberg EP, Welsh MJ. A component of innate immunity prevents bacterial biofilm development. Nature.2002; 30: 417 (6888): 552-555.
- Arsalan SY, Leung KP, Wu CD. The effect of lactoferrin on oral bacterial attachment. Oral Microbiol Immunol.2009; 24 (5):411-416.
- Goller CC, Romeo T. Environmental influences on biofilm development. Curr Top Microbiol Immunol. 2008; 322: 37-66.
- Weinberger ED. Suppression of bacterial biofilm formation by iron limitation. Med Hypotheses 2004; 63: 863-865.
- Otto M. Staphylococcal biofilms. Curr Top Microbiol Immunol. 2008; 322:207-228.
- Costerton JW, Montanaro L, Arciola CR. Biofolm in implant infections: its production and regulation. 2007; 9: 757-763