(2019) 12:87580. Cutone A, Lepanto MS, Rosa L, Scotti MJ, Rossi A, Ranucci S, et al. (2017) 545:30510. doi: 10.1111/j.1462-5822.2010.01529.x, 157. (2020) 9:e090142. 2, No. This process involves (1) synthesis of high-affinity ferric ion chelators by bacteria, (2) iron acquisition through LF or transferrin binding, mediated by bacterial-specific surface bacterial receptors, (3) or iron acquisition through bacterial reductases, which are able to reduce ferric to ferrous ions (19, 144148). Abstract Pogoutse AK, Moraes TF. (2017) 86:799823. J Vet Med Sci. doi: 10.1016/j.thromres.2012.04.017, 80. (2019) 133:217885. doi: 10.1016/j.pisc.2015.06.004, 120. doi: 10.1006/jmbi.1997.1386. doi: 10.3390/nu11102350, 40. DK edited and wrote part of the paper. Brooks CL, Arutyunova E, Lemieux MJ. Lactoferrin reduces colitis in rats via modulation of the immune system and correction of cytokine imbalance. Front Immunol. 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)]. Tang AT, Choi JP, Kotzin JJ, Yang Y, Hong CC, Hobson N, et al. Pretorius E. Platelets as potent signaling entities in type 2 diabetes mellitus. Brock JH. (2018) 44: 22438. Patel P, Shah J. (1992) 1121:1306. doi: 10.1107/S2053230X14019372, 158. Here we also suggest that LF might be used as both a preventive and therapeutic supplement in the COVID-19 pandemic, by preventing interactions between the virus and both HSPGs and possibly ACE2. 4. Aging. Nat Chem Biol. Nat Rev Drug Discov. Epub 2006 Oct 12. doi: 10.1016/j.crvi.2014.08.003, 150. Kell DB. Iron in human milk. PLoS Pathog. Cambridge: MIT Press (2006). [Epub ahead of print]. Autoimmun Rev. (2004) 89:26370. Wandersman C, Stojiljkovic I. Bacterial heme sources: the role of heme, hemoprotein receptors and hemophores. doi: 10.3390/v11070596, 102. doi: 10.1113/expphysiol.2003.026633, 132. [Epub ahead of print], 169. doi: 10.1152/ajpgi.00331.2001, 22. (1995) 23:43949. Different receptors express at vastly different levels in different tissues; thus intelectin-1 is really expressed only in the intestine (https://www.proteinatlas.org/ENSG00000179914-ITLN1/tissue), while LRP1 is far more widely distributed https://www.proteinatlas.org/ENSG00000123384-LRP1/tissue. Alzheimers Dement. Three-dimensional structure of diferric bovine lactoferrin at 2.8 A resolution. Nature. Cai X, Duan Y, Li Y, Wang J, Mao Y, Yang Z, et al. Legrand D. Overview of lactoferrin as a natural immune modulator. It is present in various body secretions such as breast milk, saliva, tears and runny nose, and the highest concentration has human colostrum. 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 . (1988) 55:118993. Women are often diagnosed later than men, likely because of menstrual blood loss. I. 8600 Rockville Pike doi: 10.1021/jacs.9b11699, 92. The use of recombinant human ACE2 (rhACE2) as ACE receptor competitor for binding has also been investigated (6, 7). It can help prevent serious complications such as liver disease, heart disease and diabetes. iron overload similar to patients with hemochromatosis [16]. sharing sensitive information, make sure youre on a federal EP wrote the paper. doi: 10.7417/CT.2019.2163, 193. Table 3. MeSH doi: 10.1038/s41440-020-0455-8. doi: 10.1292/jvms.70.313, 134. Rawat P, Kumar S, Sheokand N, Raje CI, Raje M. The multifunctional glycolytic protein glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a novel macrophage lactoferrin receptor. It is hence known to be a modulator of innate and adaptive immune responses (161). doi: 10.1210/me.2003-0456, 65. Infect Immun. doi: 10.1128/CVI.00636-12, 174. Biochim Biophys Acta. (2012) 130:e738. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. The lactoferrin receptor complex in Gram negative bacteria. (2014) 337:58195. Pink spheres represent ferric iron (Fe3+) binding sites. Pathogenesis of hereditary hemochromatosis. (2014) 70:13127. 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). doi: 10.1016/j.prosdent.2013.12.028, 58. 8. (1999) 274:70117. doi: 10.1007/s00018-005-5371-1, 62. Amersham) and plasma lactoferrin by an ELISA [5]. Shin K, Wakabayashi H, Yamauchi K, Yaeshima T, Iwatsuki K. Recombinant human intelectin binds bovine lactoferrin and its peptides. Overview of this review of lactoferrin (LF). J Virol. Neutrophil extracellular traps and the dysfunctional innate immune response of cystic fibrosis lung disease: a review. Querinjean P, Masson PL, Heremans JF. Bovine lactoferrin inhibits dengue virus infectivity by interacting with heparan sulfate, low-density lipoprotein receptor, and DC-SIGN. Lab Invest. Neuronal clearance of amyloid-beta by endocytic receptor LRP1. (2018) 2018:4308291. doi: 10.1155/2018/4308291, 57. Danzi GB, Loffi M, Galeazzi G, Gherbesi E. Acute pulmonary embolism and COVID-19 pneumonia: a random association? (2003) 50:12331. Gleerup HS, Hasselbalch SG, Simonsen AH. Metallomics. Inflammation. 8600 Rockville Pike doi: 10.1006/bioo.1995.1030. Biosci Biotechnol Biochem. Int Immunopharmacol. Role of lactobacilli and lactoferrin in the mucosal cervicovaginal defense. Intestinal inflammation is associated with, for example, some bacterial infections and, in people with inflammatory bowel disease (IBD), it is associated with disease activity and severity. (2020) 94:e00127-20. doi: 10.1111/brv.12407, 33. (2014) 6:74873. Despite the high prevalence of the gene mutation, there is a low and variable clinical penetrance. Cornish-Bowden A, Hofmeyr J-HS, Crdenas ML. (2010) 23:37786. This type I integral membrane protein receptor is a well-known receptor for respiratory viruses, and is abundantly expressed in tissues lining the respiratory tract (111). *Correspondence: Douglas B. Kell, dbk@liv.ac.uk; Etheresia Pretorius, resiap@sun.ac.za, ORCID: Douglas B. Kell orcid.org/0000-0001-5838-7963 Etheresia Pretorius orcid.org/0000-0002-9108-2384, Coronavirus Disease (COVID-19): Pathophysiology, Epidemiology, Clinical Management and Public Health Response, View all National Library of Medicine However, more than 90% of LF in human milk is in the form of apolactoferrin (160), which competes with siderophilic bacteria for ferric iron, and disrupts the proliferation of these microbial and other pathogens. When it is iron-rich it is referred to hololactoferrin and when iron-free apolactoferrin (18). (1993) 28:1306. Ballard O, Morrow AL. Platelets at the crossroads of thrombosis, inflammation and haemolysis. As well as binding it directly from the environment, bacterial siderophores can obtain iron by removing it from transferrin, lactoferrin, or ferritin (32). This attachment initiates the first contact between the cell and the virus, concentrating the virus on the cell surface, (4) followed attaching of the virus to the host receptor (ACE2) and association and entering are then facilitated via clathrin-coated pits (5) Virus replication can then happen inside the cell. The low-density lipoprotein receptor-related protein 1 is a mitogenic receptor for lactoferrin in osteoblastic cells. doi: 10.1515/CCLM.1999.049, 115. Eur J Clin Invest. Lactoferrin-containing immunocomplexes drive the conversion of human macrophages from M2- into M1-like phenotype. Genetic testing is one way to diagnose classic hemochromatosis. Iron toxicity is associated with diarrhea, reduced feed intake, and weight gain. There is no typical presentation or pathognomonic signs and symptoms of hereditary hemochromatosis. Drug Disc Today. Talukder MJ, Takeuchi T, Harada E. Receptor-mediated transport of lactoferrin into the cerebrospinal fluid via plasma in young calves. 176. Hypertens Res. The anchoring sites provided by HSPGs permit initial contact between the virus and host cells and the concentration of virus particles on cell surface. Receptor occupancy is an important characteristic of LF, when taken as supplement. doi: 10.1016/j.pcl.2012.10.002, 38. (3) Entry into host cells occur when SARS-CoV-2 first attaches to Heparan sulfate proteoglycans (HSPGs). Nutrients. Increased uptake and killing of an intracellular parasite by murine macrophages and human monocytes. J Mol Biol. doi: 10.1016/j.drudis.2012.11.008, 121. Hematology: Vol. Matsuzaki T, Nakamura M, Nogita T, Sato A. Furmanski P, Li ZP, Fortuna MB, Swamy CV, Das MR. Hemochromatosis (he-moe-kroe-muh-TOE-sis) causes your body to absorb too much iron from the food you eat. Neutrophil extracellular traps kill bacteria. doi: 10.1017/S0954422419000301. Acta Neuropathol. (2010) 6:e1000949. doi: 10.1007/s11248-012-9662-7, 186. Tfr2 results from the transcription of all exons, and is prevalently and highly expressed in hepatocytes and erythroid cell lines. In: Szallasi Z, Stelling J, Periwal V, editors. doi: 10.1007/3-540-29916-5_8, 44. Plasma lactoferrin re LbpB binds the N-lobe of lactoferrin, whereas TbpB binds the C-lobe of transferrin (157). This content is owned by the AAFP. and transmitted securely. The host defense proteome of human and bovine milk. Table 2. (2017) 8:1318. 181. Infect Immun. Semin Thromb Hemost. doi: 10.1039/c5ib00158g, 93. (2017) 98:174954. J Innate Immun. doi: 10.1016/j.autrev.2017.09.012, 140. doi: 10.1111/ggi.12776, 192. Uptake of lactoferrin by mononuclear phagocytes inhibits their ability to form hydroxyl radical and protects them from membrane autoperoxidation. Suzuki YA, Lopez V, Lnnerdal B. Mammalian lactoferrin receptors: structure and function. (2018) 41:6387. Mobilization of CD8(+) T cells via CXCR4 blockade facilitates PD-1 checkpoint therapy in human pancreatic cancer. Dis Markers. Glimvall P, Wickstrm C, Jansson H. Elevated levels of salivary lactoferrin, a marker for chronic periodontitis? Stroke. doi: 10.1111/jth.14851, 180. Modified from Rosa et al. Autosomal dominant hereditary hemochromatosis associated with a novel ferroportin mutation and unique clinical features. (2014) 5:231. doi: 10.3389/fphar.2014.00231, 123. Lactoferrin is a multi-purpose protein from the transferrin family. Watanabe T, Watanabe-Kominato K, Takahashi Y, Kojima M, Watanabe R. Adipose tissue-derived omentin-1 function and regulation. (2017) 5:1527. doi: 10.1016/j.ebiom.2016.07.012, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. Science. 105. This site needs JavaScript to work properly. Lactoferrin (LF) or lactotransferrin has recently come under the spotlight, particularly with regards to the new coronavirus pandemic that started in 2019 (COVID-19). (2018) 115:1083644. doi: 10.1016/j.jdent.2018.08.010, 51. van Leeuwen SJM, Potting CMJ, Huysmans M, Blijlevens NMA. Such a cytokine storm will significantly affect platelets, as platelets have many receptors where these inflammatory molecules may bind (173) (see Figure 5). The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Host defense proteins in breast milk and neonatal yeast colonization. Pulsatile stimulation determines timing and specificity of NF-kappaB-dependent transcription. doi: 10.1139/o01-214, 49. The benefit it might have is to reduce the oxidative stress of high iron saturation, as well as depositions. Heparan sulfate proteoglycans. Problems with the spleen, adrenal glands, pituitary gland, gallbladder or thyroid. Human milk components modulate Toll-like receptor-mediated inflammation. The test may be ordered to distinguish between IBD and non . In addition, iron overload can cause: Arthritis (joint damage). Dobson PD, Kell DB. Puddu P, Borghi P, Gessani S, Valenti P, Belardelli F, Seganti L. Antiviral effect of bovine lactoferrin saturated with metal ions on early steps of human immunodeficiency virus type 1 infection. Figure 6 shows a possible scheme on how LF might interfere with SARS-CoV-2 binding. Kell DB. Takayama Y, Aoki R, Uchida R, Tajima A, Aoki-Yoshida A. (2018) 9:37. doi: 10.3389/fimmu.2018.00037, 68. 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. (2004) 64:638. Patients with type 2 diabetes are also particularly prone to increased levels of circulating inflammatory cytokines and hypercoagulation (76). These NETs likewise modulate both acute and chronic inflammation (137, 138). Chow BD, Reardon JL, Perry EO, Laforce-Nesbitt SS, Tucker R, Bliss JM. He Y, Lawlor NT, Newburg DS. J Chem Neuroanat. Targeting the cytokine storm for therapeutic benefit. Front Microbiol. Copyright 2021 by the American Academy of Family Physicians. FASEB Bioadv. Milewska A, Nowak P, Owczarek K, Szczepanski A, Zarebski M, Hoang A, et al. Canine respiratory coronavirus, bovine coronavirus, and human coronavirus OC43: receptors and attachment factors. 400 Articles, This article is part of the Research Topic, Lactoferrin: an Important Element in Host Defense, https://www.proteinatlas.org/ENSG00000179914-ITLN1/tissue, https://www.proteinatlas.org/ENSG00000123384-LRP1/tissue, https://www.clinexprheumatol.org/abstract.asp?a=10879, Creative Commons Attribution License (CC BY). doi: 10.1016/j.bbagen.2011.10.006, 32. doi: 10.1128/JVI.01933-17, 112. Biochem Cell Biol. Trends Microbiol. (2020) 126:145674. CBD And Pain Management: Is This Supplement Right For You? (2009) 1790:6005. Superti F, Siciliano R, Rega B, Giansanti F, Valenti P, Antonini G. Involvement of bovine lactoferrin metal saturation, sialic acid and protein fragments in the inhibition of rotavirus infection. Jorch SK, Kubes P. An emerging role for neutrophil extracellular traps in noninfectious disease. Beddek AJ, Schryvers AB. A comparison of the lactoferrin- and the transferrin-mediated iron processing by monocytes is finally presented. 7. Ways by which bacteria acquire iron [adapted from (19, 30)]. Farah R, Haraty H, Salame Z, Fares Y, Ojcius DM, Said Sadier N. Salivary biomarkers for the diagnosis and monitoring of neurological diseases. 6. These symptoms are associated with a cytokine storm (166, 167) manifesting elevated serum levels of interleukin (IL) IL-1, IL-2, IL-7, IL-8, IL-9, IL-10, IL-17, granulocyte colony-stimulating factor (G-CSF), Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF), interferon (IFN), tumor necrosis factor (TNF), Interferon gamma-induced protein 10 (IP10), Monocyte Chemoattractant Protein-1 (MCP1), macrophage inflammatory protein 1(MIP1)A and MIP1B (168). The 2003 SARS-CoV strain, that also causes severe acute respiratory syndrome, attaches to host cells via host receptor ACE2 (171). 11:1221. doi: 10.3389/fimmu.2020.01221. (2018) 298:13945. BMC Immunol. Large-scale production of recombinant human lactoferrin from high-expression, marker-free transgenic cloned cows. J Neurosci. doi: 10.1016/j.mehy.2017.06.029, 190. LF is consequently a significant element of host defense (19), and its levels may vary in health and during disease. Biochem J. Sorensen M, Sorensen S. Compte Rendu des Travaux du Laboratoire de Carlsberg. (2004) 17:2314. Biochim Biophys Acta. II. This uptake then occurs mostly via the lymphatic rather than the portal circulation (131, 132). Interestingly, anticoagulant therapy, mainly with (intravenous) heparin (and mainly with low molecular weight heparin, LMWH), appears to be associated with better prognosis in severe COVID-19 patients (179). Lactoferrin clearly has immunological benefits, as well as having an important antibacterial and antiviral role. Baveye S, Elass E, Mazurier J, Spik G, Legrand D. Lactoferrin: a multifunctional glycoprotein involved in the modulation of the inflammatory process. Vargas Buonfiglio LG, Borcherding JA, Frommelt M, Parker GJ, Duchman B, Vanegas Caldern OG, et al. Marshall LJ, Oguejiofor W, Price R, Shur J. Blood LF can further be transported to the CNS via cerebrospinal fluid (133, 134) and via the Blood Brain Barrier (63, 133). doi: 10.1113/expphysiol.2006.034876, 129. (2003) 41:12733. Weinberg ED. Gao CH, Dong HL, Tai L, Gao XM. J Pediatr. In the context of its iron-binding capabilities, it means that when it binds ferric and siderophore-bound iron, it limits the availability of essential iron to microbes (27). (2017) 18:1985. doi: 10.3390/ijms18091985, 20. (2018) 10:1228. doi: 10.3390/nu10091228, 35. Microb Pathog. Liao H, Liu S, Wang H, Su H, Liu Z. doi: 10.1016/j.ijpharm.2016.09.034, 195. Xu D, Olson J, Cole JN, van Wijk XM, Brinkmann V, Zychlinsky A, et al. Kell DB, Pretorius E. To what extent are the terminal stages of sepsis, septic shock, systemic inflammatory response syndrome, and multiple organ dysfunction syndrome actually driven by a prion/amyloid form of fibrin? Bookshelf Guo W, Li M, Dong Y, Zhou H, Zhang Z, Tian C, et al. (2010) 23:48592. doi: 10.1007/s12185-017-2366-2, 28. Carrier-mediated cellular uptake of pharmaceutical drugs: an exception or the rule? Med Hypotheses. Fleming RE, Sly WS. The protein is released at high concentrations by the cells in areas of infection. Diagram created with BioRender (https://biorender.com/). PLoS Pathog. Circulating cytokines and inflammagens will hyperactivate platelets, causing low platelet count (thrombocytopenia), and a significant chance of hypercoagulation. Carro E, Bartolom F, Bermejo-Pareja F, Villarejo-Galende A, Molina JA, Ortiz P, et al. In COVID-19 infection, LF may have a role to play in not only sequestering iron and inflammatory molecules that are severely increased during the cytokine burst, but also possibly in assisting in occupying receptors and HSPGs to prevent virus binding. Korean J Physiol Pharmacol. doi: 10.1016/j.idairyj.2015.02.001, 183. Biol Blood Marrow Transplant. Adapted from Jorch and Kubes (142) and Law and Gray (143). Macrophage CD14 impacts immune defenses against influenza virus in allergic hosts. Jameson GB, Anderson BF, Norris GE, Thomas DH, Baker EN. A direct transfer of ferric iron from ceruloplasmin to lactoferrin prevents both the formation of potentially toxic hydroxyl radicals (32) and the utilization of iron by pathogenic bacteria. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. C R Biol. Front Immunol. Would you like email updates of new search results? Wang M, Sun Z, Yu T, Ding F, Li L, Wang X, et al. (2017) 95:5763. This may indicate a bacterial infection or inflammatory bowel disease (IBD). Rev Ig Bacteriol Virusol Parazitol Epidemiol Pneumoftiziol Bacteriol Virusol Parazitol Epidemiol. (2019) 11:E596. (2013) 22:5718. Anderberg RJ, Meek RL, Hudkins KL, Cooney SK, Alpers CE, Leboeuf RC, et al. Although LF is produced by the body itself, as a secretion by exocrine glands (such as maternal milk or tears) and secondary granules of human neutrophils (1), it can also be taken as a supplement, where it then acts as nutraceutical or functional food. Cell Mol Life Sci. The relatively lower risk for COVID-19 found in individuals with blood group O may be linked to a lower serum iron status in these individuals. This is not good s my understanding is it represents unbound iron floating aroundyour blood which you can have tests for TIBC (Total iron binding Content) and UIBC (Unbound Irin binding Content I believe), I have been doing nothing else and the only time my Serum ferritin was this high was when i was supping iron too fast (my serum irron tanked to about 10 when i was dumping uranium-lead) and my body could not absorb it (Floradix iron supplement) properly into serum ferritin, so suggest NIXING the lactoferrin for this reason, i mean it may kill the virus's as i think it did, but if it provokes more free floating iron..not sure how these two competing thoughts can beboth occurning, I mean I guess with a name lactoferrin..it does imply that this supplement does provide Iron..just goes to show you, all this research needs to be taken with a grain of salt, Guess I am back on earl grey regular though as tea will reduce Iron absorption, especially with meals. J Biol Chem. Nat Rev Immunol. hemochromatosis sufferers if the excess iron builds up to cause tissue damage. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Neutrophil Extracellular Traps (NETs) and their protein constituents (including lactoferrin) are released from the neutrophil. Nat Rev Drug Disc. [Epub ahead of print]. Int J Mol Sci. (2011) 6:e19433. doi: 10.1080/08820139.2016.1238925, 85. Structure of human apolactoferrin at 2.0 A resolution. Lancet. Circ Res. Biochim Biophys Acta. The primary goal of therapy is iron depletion to normalize body iron stores and to prevent or decrease organ dysfunction. Urban CF, Ermert D, Schmid M, Abu-Abed U, Goosmann C, Nacken W, et al. Kell DB, Pretorius E. Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. doi: 10.1139/o01-212, 25. Blood for lactoferrin was collected in heparin coated tubes, immediately centrifuged and plasma frozen at -25oC until analysis. Lactoferrin is a protein that protects the body . (2004) 57:2605. Another recent review (196) has also highlighted the potential utility of lactoferrin as an antiviral. (2005) 62:256075. Fransson GB, Lnnerdal B. LF acts as an important element in host defense mechanisms by binding to these receptors, but also binding to HSPG on cells, since these are locations where binding to bacteria and their cell wall products as well as viruses occur. Lactoferrin is a non-heme iron binding glycoprotein produced during lactation and by epithelial cells at mucosal surfaces. J Immunol. (2017) 18:E870. Thrombocytopenia is associated with increased risk of severe disease and mortality in patients with COVID-19, and thus serves as clinical indicator of worsening illness during hospitalization (174, 175). 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. 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