Tfr2 results from the transcription of all exons, and is prevalently and highly expressed in hepatocytes and erythroid cell lines. doi: 10.1139/o01-212, 25. Vogel S, Thein SL. However, despite these host mechanisms, pathogenic bacteria manage to multiply successfully in vivo to establish an infection. Cole AM. Outline of the normal dynamics of iron in the human body and characteristic changes induced by infection in iron metabolism. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. As well as binding it directly from the environment, bacterial siderophores can obtain iron by removing it from transferrin, lactoferrin, or ferritin (32). Keywords: lactoferrin, coronaviruses, iron, membrane receptors, HSPGs, Citation: Kell DB, Heyden EL and Pretorius E (2020) The Biology of Lactoferrin, an Iron-Binding Protein That Can Help Defend Against Viruses and Bacteria. Interestingly, 106 human neutrophils can release 15 g of LF (26). doi: 10.1161/CIRCRESAHA.120.317015. doi: 10.1039/c5ib00158g, 93. Okubo K, Kamiya M, Urano Y, Nishi H, Herter JM, Mayadas T, et al. This site needs JavaScript to work properly. (2020) 2:296303. doi: 10.1007/s10534-010-9299-z, 146. (2001) 1528:10715. LF enhances natural killer cell activity and stimulates neutrophil aggregation and adhesion in immune defense (135) and can restrict the entry of the virus into host cells during infection. Milewska A, Zarebski M, Nowak P, Stozek K, Potempa J, Pyrc K. Human coronavirus NL63 utilizes heparan sulfate proteoglycans for attachment to target cells. doi: 10.1016/S0304-4165(01)00178-7, 166. Lactoferrin reduces colitis in rats via modulation of the immune system and correction of cytokine imbalance. doi: 10.1371/journal.ppat.1000639, 142. J Chem Neuroanat. Consequently, it is common to give the bovine form rather than say a recombinant human form as a supplement. 2001 Summer;14(3):196-208; quiz 220-2. doi: 10.1007/s12185-017-2366-2, 28. The binding of LF to HSPGs prevents the first contact between virus and host cells and thus prevents subsequent infection (99). Science. LF is consequently a significant element of host defense (19), and its levels may vary in health and during disease. (2012) 130:e738. Lack of a role for iron in the Lyme disease pathogen. Hereditary hemochromatosis is usually diagnosed in the 40s or 50s. (2020) 142:238695. PMC Sci Rep. (2016) 6:25044. doi: 10.1038/srep25044, 179. Biochem Cell Biol. (1988) 55:118993. doi: 10.1016/j.idairyj.2015.02.001, 183. [Epub ahead of print]. Naskalska A, Dabrowska A, Szczepanski A, Milewska A, Jasik KP, Pyrc K. Membrane protein of human coronavirus NL63 is responsible for interaction with the adhesion receptor. Czosnykowska-ukacka M, Orczyk-Pawiowicz M, Broers B, Krlak-Olejnik B. Lactoferrin in human milk of prolonged lactation. Would you like email updates of new search results? 182. EP wrote the paper. (2018) 48(Suppl. (2011) 226:302231. Augmentation of urinary lactoferrin enhances host innate immune clearance of uropathogenic Escherichia coli. It can help prevent serious complications such as liver disease, heart disease and diabetes. 1):S312. Bacteria have, however, developed various ways to sequester iron (156). 1979 Oct-Dec;24(4):193-206. (2016) 173(Suppl.):S105. (2015) 113:358. An official website of the United States government. Koshi R, Kotani K, Ohtsu M, Yoshinuma N, Sugano N. Application of lactoferrin and 1-antitrypsin in gingival retention fluid to diagnosis of periodontal disease. MeSH Human LF is a cationic glycosylated protein consisting of 691 amino acids (9) folded into two globular lobes (80 kDa bi-lobal glycoprotein) (10), that are connected by an -helix (11, 12). Platelets at the crossroads of thrombosis, inflammation and haemolysis. Additionally, individuals affected by hemochromatosis should avoid vitamin C supplements and drink green tea, as it is a powerful chelator that works to remove iron from the body. The host defense proteome of human and bovine milk. 168. Has Lactoferrin a Role in Hereditary Hemochromatosis? Genetic testing for the hereditary hemochromatosis genes should be offered after 18 years of age to first-degree relatives of patients with the condition. doi: 10.1128/IAI.00545-15, 113. There are four types of hereditary hemochromatosis, which are categorized by the specific gene mutation involved (Table 1).1,5,6, Homozygous C282Y and heterozygous C282Y/H63D mutations of the HFE gene (iron regulatory protein) on chromosome 6 are responsible for up to 95% of hereditary hemochromatosis cases (type 1).1,3, Hereditary hemochromatosis types 2 to 4 comprise the small percentage of remaining cases and are caused by non- HFE mutations.1,5, Hereditary hemochromatosis is the most common inherited disorder among people of northern European ancestry.1,3 The United States, Europe, and Australia have a similar disease prevalence of one case per 200 to 400 people, with the highest prevalence in those of Irish and Scandinavian ancestry.1,3,5, The hereditary hemochromatosis mutation is rare in people of Asian, African, Hispanic, and Pacific Islander ancestry.7, Despite the high prevalence of the gene mutation, there is a low and variable clinical penetrance, with up to 25% of people with C282Y homozygosity being clinically asymptomatic.4,8, The clinical manifestations of iron overload typically develop in the 40s or 50s.1, The disease is equally prevalent in men and women. Front Immunol. Inhibition of the TIRAP-c-Jun interaction as a therapeutic strategy for AP1-mediated inflammatory responses. (2018) 19:42. doi: 10.1186/s12931-018-0743-x, 48. (2009) 5:e1000639. Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. Annu Rev Biochem. Though a natural component of cows' and human mothers' milk, lactoferrin is found throughout the human body.22,23 Nat Chem Biol. Bovine LF is also deemed a generally recognized as safe substance by the Food and Drug Administration (FDA, USA), and is commercially available in large quantities (19). LF is thought to exert its main biological activities following interaction with receptors on target cells. PLoS Pathog. sharing sensitive information, make sure youre on a federal Semin Thromb Hemost. Shin K, Wakabayashi H, Yamauchi K, Yaeshima T, Iwatsuki K. Recombinant human intelectin binds bovine lactoferrin and its peptides. Amino acid sequence of cysteic peptides of lactoferrin and demonstration of similarities between lactoferrin and transferrin. doi: 10.1158/1078-0432.CCR-19-0081, 84. Guo and co-workers in 2020 also found that serum levels of IL-6, C-reactive protein, serum ferritin, and D-dimer, were significantly higher in diabetic patients compared with those without, suggesting that patients with diabetes are more susceptible to an inflammatory storm eventually leading to rapid deterioration of the patient with COVID-19 (140). Kimoto Y, Nishinohara M, Sugiyama A, Haruna A, Takeuchi T. Protective effect of lactoferrin on cisplatin-induced nephrotoxicity in rats. Infect Immun. Lactoferrin actually has anti-parasitic, antiviral, anti-allergenic, anti-cancer, . They will regularly order blood tests to check iron levels.. Reghunathan R, Jayapal M, Hsu LY, Chng HH, Tai D, Leung BP, et al. Structure of human apolactoferrin at 2.0 A resolution. (2008) 116:52935. doi: 10.1099/jgv.0.000849, 152. Nat Rev Rheumatol. Lactoferrin sources as supplements, and examples where it has been used to treat various conditions. Takeuchi T, Kitagawa H, Harada E. Evidence of lactoferrin transportation into blood circulation from intestine via lymphatic pathway in adult rats. Adv Nutr. Aerosolized bovine lactoferrin counteracts infection, inflammation and iron dysbalance in a cystic fibrosis mouse model of Pseudomonas aeruginosa chronic lung infection. Front Pharmacol. Fernandes KE, Carter DA. (2017) 6:CD007137. PLoS ONE. CBD And Pain Management: Is This Supplement Right For You? Because of increased awareness and earlier diagnosis, the end-organ damage secondary to iron overload is not often seen in clinical practice. . Biometals. doi: 10.1107/S2053230X14019372, 158. Vargas Buonfiglio LG, Borcherding JA, Frommelt M, Parker GJ, Duchman B, Vanegas Caldern OG, et al. Diabetes is a risk factor for the progression and prognosis of COVID-19. Such binding evokes signaling systems and pathways involving, amongst others, mitogen-activated protein kinase (MAPK) (105), NF-B (106), activator protein 1 (AP-1) (107), and various interferon regulatory factors (IRFs) [for a comprehensive review see (108)]. LF has strong antiviral activity against a broad spectrum of both naked and enveloped DNA and RNA viruses (99, 149151). Lactoferrin helps regulate how. Heparan sulfate proteoglycans: structure, protein interactions and cell signaling. LF binds one ferric iron atom in each of its two lobes; however, an important attribute is that it does not release its iron, even at pH 3.5. Zenewicz LA. The .gov means its official. It is the most common inherited disorder among people of northern European ancestry. (2018) 9:37. doi: 10.3389/fimmu.2018.00037, 68. Sci Rep. (2017) 7:10733. doi: 10.1038/s41598-017-11462-z, 187. Superti-Furga G, Lackner D, Wiedme T, Ingles-Prieto A, Barbosa B, Girardi E, et al. (2020) 94:e00127-20. Lactoferrin, as a protein, is far too large to exploit such a route, and instead passes from the stomach via epithelial cells and into the blood using endocytosis (125, 126), especially via Peyer's patches (127), and when it is encapsulated (enterically formulated) in liposomes (128130). Women typically present later in life when they are postmenopausal, likely because of menstrual blood loss delaying the development of symptomatic iron overload.1,3, Genetic testing for the C282Y and H63D mutations of the HFE gene is recommended for first-degree relatives of people with hereditary hemochromatosis; screening does not need to begin until 18 years of age because clinical manifestations are rare before this age.1,3, Population-level genetic testing or laboratory screening for hereditary hemochromatosis is not recommended because of the cost and the variable prevalence and incomplete penetrance of the C282Y mutation.1,35,9, The presentation of hereditary hemochromatosis varies, with biochemical expression occurring first and clinical expression occurring in later stages of disease.3,8 Table 2 summarizes the stages of hereditary hemochromatosis.1,2,4,5, The differential diagnosis includes other causes of secondary iron overload via excess absorption and organ deposition of iron (Table 3).15,10, Hereditary hemochromatosis should be considered in the differential diagnosis of patients with elevated liver enzymes and abnormal iron study results.24,11. Trans-endothelial and trans-epithelial transfer of lactoferrin into the brain through BBB and BCSFB in adult rats. It has important immunological properties, and is both antibacterial and antiviral. Biochim Biophys Acta. J Am Chem Soc. Biochim Biophys Acta. Perspect Sci. The biology of ergothioneine, an antioxidant nutraceutical. (1998) 66:48691. Blood for lactoferrin was collected in heparin coated tubes, immediately centrifuged and plasma frozen at -25oC until analysis. 2, No. An Acad Bras Cienc. Unable to load your collection due to an error, Unable to load your delegates due to an error. doi: 10.1016/j.thromres.2012.04.017, 80. LF plays an important role in host defense, upon its release from the neutrophil (26). (2003) 65:95764. PMC With regard to its iron binding properties, lactoferrin differs F. Study on the effects of an oral lactobacilli and lactoferrin complex in women with intermediate vaginal microbiota. Blood LF can further be transported to the CNS via cerebrospinal fluid (133, 134) and via the Blood Brain Barrier (63, 133). (2004) 89:26370. Ward PP, Uribe-Luna S, Conneely OM. Togawa J, Nagase H, Tanaka K, Inamori M, Umezawa T, Nakajima A, et al. Kell DB, Dobson PD, Bilsland E, Oliver SG. doi: 10.18632/aging.103100, 5. doi: 10.1113/expphysiol.2006.034876, 129. Treating hemochromatosis can help relieve symptoms of tiredness, stomach pain and skin darkening. doi: 10.1016/S0968-0004(03)00031-8, 163. Kai H, Kai M. Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors-lessons from available evidence and insights into COVID-19. LF inhibits the entry of viral particles into host cells, either by direct attachment to the viral particles or by blocking their cellular receptors (discussed in previous paragraphs) (149). Acta Crystallogr F Struct Biol Commun. (2017) 46:190200. Biochim Biophys Acta. There are also three different isoforms: LF- is the iron-binding isoform, while LF- and LF-g both have ribonuclease activity but do not bind iron (11, 17). Anderberg RJ, Meek RL, Hudkins KL, Cooney SK, Alpers CE, Leboeuf RC, et al. Autosomal dominant hereditary hemochromatosis associated with a novel ferroportin mutation and unique clinical features. Tfr2 cDNA is 2.3 kb long (AF067864), and the Tfr2 is a protein of about 89 kDa encompassing 801 amino acids [].As Tfr1, Tfr2 has a short cytoplasmic tail (aa 1-80) that contains a consensus sequence YQRV for endocytosis, a transmembrane domain (aa 81 . Furmanski P, Li ZP, Fortuna MB, Swamy CV, Das MR. Rev Ig Bacteriol Virusol Parazitol Epidemiol Pneumoftiziol Bacteriol Virusol Parazitol Epidemiol. Biochim Biophys Acta. Harada E, Itoh Y, Sitizyo K, Takeuchi T, Araki Y, Kitagawa H. Characteristic transport of lactoferrin from the intestinal lumen into the bile via the blood in piglets. J Pediatr. (2012) 90:32938. (1998) 30:105562. The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s. Ishikado A, Imanaka H, Takeuchi T, Harada E, Makino T. Liposomalization of lactoferrin enhanced it's anti-inflammatory effects via oral administration. American College of Gastroenterology expert consensus guideline, Expert opinion (serum ferritin goal varies based on recommending organization), American College of Medical Genetics and Genomics, Type 1A hereditary hemochromatosis (homozygote), Arthropathy, skin pigmentation, diabetes mellitus, endocrine dysfunction, cardiomyopathy, hypogonadism, Arthropathy, skin pigmentation, diabetes, endocrine dysfunction, cardiomyopathy, hypogonadism, Possible elevations of serum iron/ferritin, no evidence of tissue iron deposition, Type 2 (juvenile hereditary hemochromatosis), Early onset (< 30 years of age), hypogonadism, cardiomyopathy, Iron deposition in the spleen, anemia, fatigue, joint pain, Immediate, unlimited access to all AFP content, Immediate, unlimited access to this issue's content, Immediate, unlimited access to just this article. Clin Chim Acta. 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