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Id Subject Object Predicate Lexical cue
T1 0-101 Sentence denotes The Biology of Lactoferrin, an Iron-Binding Protein That Can Help Defend Against Viruses and Bacteria
T2 103-111 Sentence denotes Abstract
T3 112-174 Sentence denotes Lactoferrin is a nutrient classically found in mammalian milk.
T4 175-296 Sentence denotes It binds iron and is transferred via a variety of receptors into and between cells, serum, bile, and cerebrospinal fluid.
T5 297-380 Sentence denotes It has important immunological properties, and is both antibacterial and antiviral.
T6 381-517 Sentence denotes In particular, there is evidence that it can bind to at least some of the receptors used by coronaviruses and thereby block their entry.
T7 518-785 Sentence denotes Of importance are Heparan Sulfate Proteoglycans (HSPGs) and the host receptor angiotensin-converting enzyme 2 (ACE2), as based on other activities lactoferrin might prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from attaching to the host cells.
T8 786-970 Sentence denotes Lactoferrin (and more specifically enteric-coated LF because of increased bioavailability) may consequently be of preventive and therapeutic value during the present COVID-19 pandemic.
T9 972-984 Sentence denotes Introduction
T10 985-1151 Sentence denotes Lactoferrin (LF) or lactotransferrin has recently come under the spotlight, particularly with regards to the new coronavirus pandemic that started in 2019 (COVID-19).
T11 1152-1277 Sentence denotes Diet and supplements support a well-functioning immune system, and favorably influence the body's ability to fight infection.
T12 1278-1531 Sentence denotes 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.
T13 1532-1590 Sentence denotes Our particular focus is on its role as an oral supplement.
T14 1591-1817 Sentence denotes Here we also collate some of the evidence that shows how LF may be an important nutrient to support host immunity, including as an antibacterial and antiviral agent, but particularly with the current COVID-19 pandemic in mind.
T15 1818-1957 Sentence denotes We summarize what is already known about LF, including its immunological properties, as well as its antibacterial and antiviral activities.
T16 1958-2061 Sentence denotes We also discuss how LF uses Heparan Sulfate Proteoglycans (HSPGs) on cell surfaces to facilitate entry.
T17 2062-2263 Sentence denotes This is of particular importance to coronaviruses, as these viruses are considered to bind to the host cell by attaching first to HSPGs using them as preliminary docking sites on the host cell surface.
T18 2264-2428 Sentence denotes LF is known to interfere with some of the receptors used by coronaviruses, it may thus contribute usefully to the prevention and treatment of SARS CoV-2 infections.
T19 2429-2663 Sentence denotes In COVID-19 infection, LF may therefore have a role to play, not only sequestering iron and inflammatory molecules that are severely increased during the cytokine burst, but also possibly in assisting by occupying receptors and HSPGs.
T20 2664-2838 Sentence denotes LF might also prevent virus accumulation by the host cell, as well as rolling activity and entering of the virus via the host receptor angiotensin-converting enzyme 2 (ACE2).
T21 2839-3022 Sentence denotes It has been 20 years since the discovery of ACE2, and since its discovery it has been found to be expressed in numerous tissues, including the lungs and the cardiovascular system (2).
T22 3023-3174 Sentence denotes During 2020, there has been a renewed interest in this receptor, due to the interactions of novel coronaviruses and their interactions with ACE2 (3–5).
T23 3175-3291 Sentence denotes South and co-workers in 2020 also investigated whether ACE2 blockade is a suitable option to attenuate COVID-19 (5).
T24 3292-3408 Sentence denotes The use of recombinant human ACE2 (rhACE2) as ACE receptor competitor for binding has also been investigated (6, 7).
T25 3409-3576 Sentence denotes There is also interest in the therapeutic targeting of HSPGs, and Hondermarck and co-workers suggested that is seems an easy way to inhibit SARS-Cov-2 infectivity (8).
T26 3577-3772 Sentence denotes 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.
T27 3773-3823 Sentence denotes We summarize the layout of this paper in Figure 1.
T28 3824-3878 Sentence denotes Figure 1 Overview of this review of lactoferrin (LF).
T29 3879-4264 Sentence denotes We discuss (1) discovery and structure of LF; (2) LF membrane receptors and some of the bacteria, their products and viruses that might also bind to these receptors, (3) including how acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (causing COVID-19) may interact with host cells (see Figure 6 and Conclusion for a detailed discussion); (4) and how LF assists with host immunity.
T30 4265-4316 Sentence denotes Diagram created with BioRender (www.biorender.com).
T31 4318-4341 Sentence denotes Discovery and Structure
T32 4342-4530 Sentence denotes 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 α-helix (11, 12).
T33 4531-4571 Sentence denotes Bovine LF contains 689 amino acids (13).
T34 4572-4745 Sentence denotes LF was first discovered and isolated from bovine milk in 1939 (14), and is a member of the transferrin family (60% amino acid sequence identity with serum transferrin) (11).
T35 4746-4970 Sentence denotes LF and transferrin have similar amino acid compositions, secondary structures (including their disulphide linkages), and tertiary structures, although they differ in terms of biological functions (11, 15, 16) (see Figure 2).
T36 4971-5129 Sentence denotes There are also three different isoforms: LF-α is the iron-binding isoform, while LF- β and LF-g both have ribonuclease activity but do not bind iron (11, 17).
T37 5130-5224 Sentence denotes When it is iron-rich it is referred to hololactoferrin and when iron-free apolactoferrin (18).
T38 5225-5462 Sentence denotes The tertiary structures of the two forms are significantly different: apolactoferrin is characterized by an open conformation of the N-lobe and a closed conformation of the C-lobe, while both lobes are closed in the hololactoferrin (18).
T39 5463-5651 Sentence denotes Human LF and bovine LF possess high sequence homology and have very similar antibacterial, antifungal, antiviral, antiparasitic, anti-inflammatory, and immunomodulatory activities (19–21).
T40 5652-5760 Sentence denotes Consequently, it is common to give the bovine form rather than say a recombinant human form as a supplement.
T41 5761-5932 Sentence denotes 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).
T42 5933-6065 Sentence denotes Figure 2 Crystal structures of bovine lactoferrin (PDB code = 1BLF), human lactoferrin (1B0L), and rabbit serum transferrin (1JNF).
T43 6066-6090 Sentence denotes Adapted from Vogel (10).
T44 6091-6147 Sentence denotes Pink spheres represent ferric iron (Fe3+) binding sites.
T45 6148-6351 Sentence denotes Due to its similarities to transferrin, which is the main iron transporting molecule in serum (22, 23), α-LF possesses iron binding capabilities (24, 25), and it can chelate two ferric irons (Fe3+) (26).
T46 6352-6493 Sentence denotes 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.
T47 6494-6617 Sentence denotes This is of importance as this property assures iron sequestration in infected tissues where the pH is commonly acidic (27).
T48 6618-6792 Sentence denotes 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).
T49 6793-6986 Sentence denotes In healthy individuals, iron is largely intracellular and sequestered within ferritin or as a co-factor of cytochromes and FeS proteins, and as haem complexed to hemoglobin within erythrocytes.
T50 6987-7045 Sentence denotes Circulating iron is rapidly bound by transferrin (28, 29).
T51 7046-7198 Sentence denotes When erythrocytes lyse and hemoglobin or haem is released into the circulation, their hemoglobin is captured by haptoglobin, and haem by hemopexin (30).
T52 7199-7385 Sentence denotes Here, circulating serum ferroxidase ceruloplasmin is of importance, as LF can bind to ceruloplasmin, such that a direct transfer of ferric iron between the two proteins is possible (31).
T53 7386-7576 Sentence denotes 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.
T54 7577-7778 Sentence denotes LF is therefore an important player in preventing bacteria from acquiring and sequestering iron, which [with the possible exception of Borrelia burgdorferi (33)]; they require for growth and virulence.
T55 7779-7893 Sentence denotes LF also acts as biomarker, as it is commonly upregulated when the host is suffering from various kinds of disease.
T56 7894-7930 Sentence denotes See Table 1 for selected references.
T57 7931-8050 Sentence denotes Table 1 Lactoferrin as a major player in host defense and iron binding, and its use as biomarker for various diseases.
T58 8051-8078 Sentence denotes Area of action References
T59 8079-8123 Sentence denotes Protecting neonates via breast milk (34–41)
T60 8124-8242 Sentence denotes LF in cervicovaginal mucosa and female reproductive tract; antibacterial, antifungal antiparasitic, antiviral (42–45)
T61 8243-8270 Sentence denotes LF in the airways (46, 47)
T62 8271-8327 Sentence denotes Mucosal surfaces, allergen-induces skin infections (48)
T63 8328-8380 Sentence denotes Neutrophil extracellular trap (NET) production (49)
T64 8381-8446 Sentence denotes Saliva and its antimicrobial activities and iron binding (50–52)
T65 8447-8501 Sentence denotes Saliva as biomarker for neurological diseases (53–55)
T66 8502-8571 Sentence denotes Saliva as biomarker for periodontal disease and oral dryness (56–59)
T67 8573-8611 Sentence denotes Lactoferrin and Its Membrane Receptors
T68 8612-8719 Sentence denotes LF is thought to exert its main biological activities following interaction with receptors on target cells.
T69 8720-8823 Sentence denotes There are in fact many LF receptors, though sometimes one is referred to as “the” lactoferrin receptor.
T70 8824-8946 Sentence denotes They have been detected in multiple tissues and cell types including intestinal epithelial cells and lymphocytes (60, 61).
T71 8947-9162 Sentence denotes Receptors that bind LF include CD14 (62), LDL receptor-related protein-1 (LRP-1/CD91) (63–65) intelectin-1 (omentin-1) (66), Toll-like receptor 2 and 4 (TLR4) (67) and cytokine receptor 4 (CXCR4) (68) (see Table 2).
T72 9163-9412 Sentence denotes Importantly, LF also binds to heparan sulfate proteoglycans (HSPGs), which are cell-surface and extracellular matrix macromolecules that are composed of a core protein decorated with covalently linked glycosaminoglycan (GAG) chains (86, 87, 98, 99).
T73 9413-9425 Sentence denotes See Table 2.
T74 9426-9723 Sentence denotes 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.
T75 9724-9929 Sentence denotes These multiple receptors arguably underpin the substantial and widespread effects that LF can induce, since only when multiple targets are hit simultaneously can one normally have major effects (103, 104).
T76 9930-10080 Sentence denotes Table 2 Receptors for lactoferrin, cells where these receptors are present, and other molecules and/or components that might bind to these receptors.
T77 10081-10167 Sentence denotes Receptor for lactoferrin Cell types where receptor are present Selected references
T78 10168-10404 Sentence denotes Lactoferrin receptor/LRP-1/CD91/apoE receptor or the chyclomicron remnant receptor Multiple tissues and cell types including intestinal epithelial cell lymphocytes, fibroblasts, neurons, hepatocytes, endothelial cells (62) (60, 69–71)
T79 10405-10577 Sentence denotes Intelectin-1 (omentin-1) Visceral (omental and epicardial) fat, mesothelial cells, vascular cells, airway goblet cells, small intestine, colon, ovary, and plasma (66, 72)
T80 10578-10643 Sentence denotes TLR2 and TLR4 Endothelial cells, platelets, neutrophils (73–80)
T81 10644-10714 Sentence denotes CXCR4 Platelets, endothelial cells, neutrophils, T-cells (78, 81–83)
T82 10715-10759 Sentence denotes CD14 Macrophages, neutrophils (62, 84, 85)
T83 10760-10871 Sentence denotes Heparan sulfate proteoglycans (HSPGs), Epithelial cells, endothelial cells, fibroblasts, lymphocytes (86, 87)
T84 10872-10900 Sentence denotes Interleukin 1 Various cells
T85 10901-10985 Sentence denotes Selected molecules and entities that bind to these receptors, other than lactoferrin
T86 10986-11037 Sentence denotes Receptor Molecule or cellular entity References
T87 11038-11074 Sentence denotes Lactoferrin receptor Bacteria (30)
T88 11075-11112 Sentence denotes LRP-1 Amyloid beta (Aβ) (69, 88–90)
T89 11113-11315 Sentence denotes Intelectin-1 (omentin-1) Microbial sugars, including β-D-galactofuranose (β-Galf), D-glycerol 1-phosphate, d-glycero-D-talo-oct-2-ulosonic acid (KO), and 3-deoxy-d-manno-oct-2-ulosonic acid (KDO) (91)
T90 11316-11386 Sentence denotes TLR4 Bacterial lipopolysaccharides (LPSs) Herpex simplex (78, 92–94)
T91 11387-11431 Sentence denotes CXCR4 Viruses (including HIV) (78, 95, 96)
T92 11432-11473 Sentence denotes CD14 LPS, H7N9 Influenza virus (92, 97)
T93 11474-11687 Sentence denotes Heparan sulfate proteoglycans (HSPGs) Various viruses, including HIV and SARS-CoV (86, 87, 98–102) The entry of bacteria, bacterial products or viruses into host cells may also occur via some of these receptors.
T94 11688-11948 Sentence denotes Such binding evokes signaling systems and pathways involving, amongst others, mitogen-activated protein kinase (MAPK) (105), NF-κB (106), activator protein 1 (AP-1) (107), and various interferon regulatory factors (IRFs) [for a comprehensive review see (108)].
T95 11949-12153 Sentence denotes During infection, activation of these signaling pathways results in a cellular response that shares multiple cytoplasmic components, leading ultimately to the activation of a complex biomolecular network.
T96 12154-12331 Sentence denotes Phosphorylation of relevant substrates (e.g., enzymes, microtubules, histones, and transcription factors) plays a crucial role in determining the host's cellular response (109).
T97 12332-12479 Sentence denotes Viruses (110, 111), as well as bacteria (112), interact with and bind to HSPGs, using this proteoglycan as entry into the cell (see also Figure 1).
T98 12480-12711 Sentence denotes 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.
T99 12712-12839 Sentence denotes The membrane-penetrating peptide HIV-tat, released from HIV-infected cells, also enters surrounding cells using HSPGs (86, 98).
T100 12840-12993 Sentence denotes This binding capacity allows LF to compete with such molecules for receptor occupancy (113, 114), and therefore plays a vital role in host immunity (20).
T101 12994-13064 Sentence denotes LF can also serve to prevent nephrotoxicity, e.g., of cisplatin (115).
T102 13066-13087 Sentence denotes Lactoferrin Transport
T103 13088-13218 Sentence denotes Small molecules, including pharmaceutical drugs, require solute carriers of the SLC family (116) to effect their uptake (117–124).
T104 13219-13510 Sentence denotes 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 (128–130).
T105 13511-13606 Sentence denotes This uptake then occurs mostly via the lymphatic rather than the portal circulation (131, 132).
T106 13607-13665 Sentence denotes LF can also enter, and be reabsorbed from, the bile (125).
T107 13666-13790 Sentence denotes Blood LF can further be transported to the CNS via cerebrospinal fluid (133, 134) and via the Blood Brain Barrier (63, 133).
T108 13792-13841 Sentence denotes Lactoferrin: an Important Element in Host Defense
T109 13843-13870 Sentence denotes Neutrophils and Lactoferrin
T110 13871-13957 Sentence denotes LF plays an important role in host defense, upon its release from the neutrophil (26).
T111 13958-14101 Sentence denotes LF also enhances natural killer cell activity in immune defense (135) and can restrict the entry of the virus into host cells during infection.
T112 14102-14242 Sentence denotes As part of the host's inflammatory response, leucocytes, including neutrophils, release LF from their granules, where it is normally stored.
T113 14243-14399 Sentence denotes Activated neutrophils also release chromatin fibers, known as neutrophil extracellular traps (NETs), which trap and kill, amongst others, bacteria (1, 136).
T114 14400-14476 Sentence denotes These NETs likewise modulate both acute and chronic inflammation (137, 138).
T115 14477-14600 Sentence denotes NETs are also found in various autoimmune conditions such as rheumatoid arthritis, systemic lupus erythematosus (139, 140).
T116 14601-14667 Sentence denotes Interestingly, 106 human neutrophils can release 15 μg of LF (26).
T117 14668-14809 Sentence denotes In addition to DNA and histones, NET fibers contain extranuclear proteins and proteins such as elastase, myeloperoxidase (MPO), and LF (141).
T118 14810-14953 Sentence denotes LF may also serve as an intrinsic inhibitor of NETs release into the circulation, and may therefore be central in controlling NETs release (1).
T119 14954-14967 Sentence denotes See Figure 3.
T120 14968-15282 Sentence denotes Figure 3 Bacterial binding to various receptors, e.g., Toll-like receptors 2 and 4 (TLR2 and 4), as well as complement receptors, leads to protein arginine deiminase 4 (PAD4) activation, followed by chromatin decondensation, hypercitrullination of histones 3 and 4 in the nucleus, and nuclear membrane disruption.
T121 15283-15317 Sentence denotes Granules also release lactoferrin.
T122 15318-15444 Sentence denotes Neutrophil Extracellular Traps (NETs) and their protein constituents (including lactoferrin) are released from the neutrophil.
T123 15445-15503 Sentence denotes Adapted from Jorch and Kubes (142) and Law and Gray (143).
T124 15504-15550 Sentence denotes Bacteria are expelled and trapped in the NETs.
T125 15551-15607 Sentence denotes Diagram created with BioRender (https://biorender.com/).
T126 15609-15633 Sentence denotes Bacteria and Lactoferrin
T127 15634-15825 Sentence denotes One of the most well-known characteristics of LF is that it is antibacterial (19, 144–148), antiviral (99, 149–151), antifungal (152–154), anti-inflammatory (26), and anti-carcinogenic (155).
T128 15826-15924 Sentence denotes Its ability to of limit iron availability to microbes is one of its crucial amicrobial properties.
T129 15925-15996 Sentence denotes Bacteria have, however, developed various ways to sequester iron (156).
T130 15997-16168 Sentence denotes Figure 4 shows how bacteria acquire iron through receptor-mediated recognition of transferrin, hemopexin, hemoglobin, or hemoglobin-haptoglobin complexes and also LF (30).
T131 16169-16324 Sentence denotes As well as binding it directly from the environment, bacterial siderophores can obtain iron by removing it from transferrin, lactoferrin, or ferritin (32).
T132 16325-16413 Sentence denotes These siderophore-iron complexes are then recognized by receptors on the bacterium (30).
T133 16414-16652 Sentence denotes Host innate immune functions are supported by the circulating protein, siderocalin, also known as Neutrophil gelatinase-associated lipocalin (NGAL), lipocalin2 or Lcn2 as it inhibits siderophore-mediated iron acquisition and release (30).
T134 16653-16723 Sentence denotes Figure 4 Ways by which bacteria acquire iron [adapted from (19, 30)].
T135 16724-16818 Sentence denotes Transferrin receptor, lactoferrin receptor, hemophore (Hp), hemophore receptor, and hemopexin.
T136 16819-16918 Sentence denotes Siderophores remove iron from lactoferrin, ferritin and transferrin, and also from the environment.
T137 16919-17001 Sentence denotes Stealth siderophores are modified in such a way as to prevent siderocalin binding.
T138 17002-17098 Sentence denotes A primary bacterial defense against siderocalin involves the production of stealth siderophores.
T139 17099-17144 Sentence denotes Modified from Rosa et al. and Skaar (19, 30).
T140 17145-17201 Sentence denotes Diagram created with BioRender (https://biorender.com/).
T141 17202-17368 Sentence denotes Although LF has various means to counteract bacteria as part of its immune function (131), it is also capable of being hijacked to benefit the activities of bacteria.
T142 17369-17447 Sentence denotes Thus, bacteria can also exploit LF by removing its bound ferric iron (19, 30).
T143 17448-17767 Sentence denotes 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, 144–148).
T144 17768-17952 Sentence denotes Several Gram-negative pathogens including members of the genera Neisseria and Moraxella have evolved two-component systems that can extract iron from the host LF and transferrin (157).
T145 17953-18026 Sentence denotes N. meningitidis is a principal cause of bacterial meningitis in children.
T146 18027-18273 Sentence denotes While the majority of pathogenic bacteria employ siderophores to chelate and scavenge iron (158), Neisseria has evolved a series of protein transporters that directly hijack iron sequestered in host transferrin, lactoferrin, and hemoglobin (159).
T147 18274-18576 Sentence denotes The system consists of a membrane-bound transporter that extracts and transports iron across the outer membrane (TbpA for transferrin and LbpA for lactoferrin), and a lipoprotein that delivers iron-loaded lactoferrin/transferrin to the transporter (TbpB for transferrin and LbpB for lactoferrin) (157).
T148 18577-18666 Sentence denotes LbpB binds the N-lobe of lactoferrin, whereas TbpB binds the C-lobe of transferrin (157).
T149 18667-18879 Sentence denotes 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.
T150 18880-18966 Sentence denotes Similarly LF supplements may play an important role to counteract bacterial processes.
T151 18967-19083 Sentence denotes LF is consequently a significant element of host defense (19), and its levels may vary in health and during disease.
T152 19084-19166 Sentence denotes It is hence known to be a modulator of innate and adaptive immune responses (161).
T153 19168-19191 Sentence denotes Viruses and Lactoferrin
T154 19192-19312 Sentence denotes LF has strong antiviral activity against a broad spectrum of both naked and enveloped DNA and RNA viruses (99, 149–151).
T155 19313-19503 Sentence denotes 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).
T156 19504-19690 Sentence denotes Some of the viruses that LF prevents from entering host cells e.g., Herpes simplex virus (162), human papillomavirus (163), human immunodeficiency virus (HIV) (164), and rotavirus (165).
T157 19691-19829 Sentence denotes These viruses typically utilize common molecules on the cell membrane to facilitate their invasion into cells, including HSPGs (Figure 1).
T158 19830-19963 Sentence denotes HSPGs provide the first anchoring sites on the host cell surface, and help the virus make primary contact with these cells (99, 162).
T159 19964-20062 Sentence denotes HSPGs can be either membrane bound, or in secretory vesicles and in the extracellular matrix (86).
T160 20063-20169 Sentence denotes It has been shown that LF is able to prevent the internalization of some viruses by binding to HSPGs (86).
T161 20171-20195 Sentence denotes COVID-19 and Lactoferrin
T162 20196-20279 Sentence denotes COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
T163 20280-20446 Sentence denotes Many COVID-19 patients develop acute respiratory distress syndrome (ARDS), which leads to pulmonary edema and lung failure, and have liver, heart, and kidney damages.
T164 20447-20908 Sentence denotes These symptoms are associated with a cytokine storm (166, 167) manifesting elevated serum levels of interleukin (IL) IL-1β, 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)γ, tumor necrosis factor (TNF)α, Interferon gamma-induced protein 10 (IP10), Monocyte Chemoattractant Protein-1 (MCP1), macrophage inflammatory protein 1(MIP1)A and MIP1B (168).
T165 20909-21007 Sentence denotes IL-22, in collaboration with IL-17 and TNFα, induces antimicrobial peptides in the mucosal organs.
T166 21008-21278 Sentence denotes IL-22 also upregulates mucins, fibrinogen, anti-apoptotic proteins, serum amyloid A, and LPS binding protein (169); therefore, IL-22 may contribute to the formation of life-threatening oedema with mucins and fibrin (170), seen in SARS-CoV-22 and SARS-CoV patients (168).
T167 21279-21409 Sentence denotes The 2003 SARS-CoV strain, that also causes severe acute respiratory syndrome, attaches to host cells via host receptor ACE2 (171).
T168 21410-21581 Sentence denotes 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).
T169 21582-21671 Sentence denotes During COVID-19 infection, SARS-CoV-2 also enters host cells via the ACE2 receptor (172).
T170 21672-21844 Sentence denotes ACE2 is highly expressed on human lung alveolar epithelial cells, enterocytes of the small intestine, and the brush border of the proximal tubular cells of the kidney (99).
T171 21845-21992 Sentence denotes HSPGs are also one of the preliminary docking sites on the host cell surface and play an important role in the process of SARS-CoV cell entry (99).
T172 21993-22137 Sentence denotes There is no current confirmed information that SARS-CoV-2 binds to HSPGs, however, LF blocks the infection of SARS-CoV by binding to HSPGs (99).
T173 22138-22221 Sentence denotes It is not presently known whether LF binds to ACE2, but it does bind to HSPGs (99).
T174 22222-22358 Sentence denotes Whether SARS-CoV-2 also enters host cells via HPSGs in the same way, as does (the 2003) SARS-CoV clearly warrants further investigation.
T175 22359-22482 Sentence denotes Of particular interest, and in the context of this paper, is the set of interactions between SARS-CoV-2 and host platelets.
T176 22483-22587 Sentence denotes This is of importance, as COVID-19 infection, can cause hyperinflammation due to a cytokine storm (166).
T177 22588-22701 Sentence denotes Pathogens like the influenza virus and Francisella tularensis, do trigger life-threatening cytokine storms (173).
T178 22702-22859 Sentence denotes Such a cytokine storm will significantly affect platelets, as platelets have many receptors where these inflammatory molecules may bind (173) (see Figure 5).
T179 22860-23021 Sentence denotes Circulating cytokines and inflammagens will hyperactivate platelets, causing low platelet count (thrombocytopenia), and a significant chance of hypercoagulation.
T180 23022-23225 Sentence denotes 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).
T181 23226-23368 Sentence denotes Patients with type 2 diabetes are also particularly prone to increased levels of circulating inflammatory cytokines and hypercoagulation (76).
T182 23369-23553 Sentence denotes COVID-19 patients without other comorbidities but with diabetes are at higher risk of severe pneumonia, excessive uncontrolled inflammatory responses and a hypercoagulable state (176).
T183 23554-23906 Sentence denotes 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).
T184 23907-23983 Sentence denotes Acute pulmonary embolism has also been reported in COVID-19 infection (177).
T185 23984-24123 Sentence denotes Focal accumulation of activated platelets within the oedematous area ex vivo correlated well with the size of the pulmonary embolism (178).
T186 24124-24331 Sentence denotes 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).
T187 24332-24568 Sentence denotes Figure 5 Simplified platelet signaling and receptor activation during disease with main dysregulated molecules thrombin, fibrin(ogen), von Willebrand Factor (vWF) interleukins (IL) like IL-1α, IL-1β, and IL17A and cytokines like TNF-α.
T188 24569-24625 Sentence denotes Diagram created with BioRender (https://biorender.com/).
T189 24626-24877 Sentence denotes 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.
T190 24878-24960 Sentence denotes Receptor occupancy is an important characteristic of LF, when taken as supplement.
T191 24961-25088 Sentence denotes Furthermore, it may assist in preventing thrombocytopenia, and hypercoagulation, both prominent features of COVID-19 infection.
T192 25090-25120 Sentence denotes Lactoferrin as a Nutraceutical
T193 25121-25438 Sentence denotes There is little doubt that oral LF can be of health benefit to the host, and while it is not considered to be absolutely necessary for mammalian life (so it is not a vitamin), it is reasonable to class it as a nutraceutical along with a variety of other molecules such as those mentioned in various papers (180, 181).
T194 25439-25584 Sentence denotes As a nutraceutical, the bioavailability of LF would clearly be an important consideration in its use for the prevention or treatment of COVID-19.
T195 25585-25750 Sentence denotes Enteric coating of LF capsules has been proposed as a measure to maximize the uptake of LF by the receptors located in the brush-border of the small intestine (182).
T196 25751-26011 Sentence denotes Enteric coating allows LF release some distance from LF-degrading pepsin activities in the stomach, allowing it to remain intact, in the form capable of binding small intestinal LF receptors for uptake and eventual transfer into the systemic circulation (182).
T197 26012-26188 Sentence denotes In a rodent study, the “absorption” of enteric-formulated LF was approximately 10-fold higher than that of regular LF introduced into the stomach of experimental animals (128).
T198 26189-26461 Sentence denotes In view of these investigations, the authors of this paper regard enteric-coated LF as superior to regular LF supplements with respect to bioavailability and potential application for the prevention or therapy for coronaviruses such as the SARS-Cov-2 involved in COVID-19.
T199 26463-26535 Sentence denotes Nutritional Sources, Availability and Uses for Lactoferrin as Supplement
T200 26536-26603 Sentence denotes There is considerable LF availability in various forms and sources.
T201 26604-26720 Sentence denotes Table 3 shows some of the sources and the references to research where it has been used to treat various conditions.
T202 26721-26830 Sentence denotes Table 3 Lactoferrin sources as supplements, and examples where it has been used to treat various conditions.
T203 26831-26865 Sentence denotes Lactoferrin sources as supplements
T204 26866-26886 Sentence denotes Product References
T205 26887-27031 Sentence denotes Bovine and human milk Morinaga Industries in Japan (183) DoMO Food Ingredients, a subsidiary of Friesland Dairy Foods, in the Netherlands (184)
T206 27032-27122 Sentence denotes Human recombinant lactoferrin Talactoferrin from Agennix, Inc., Houston, Texas, USA (184)
T207 27123-27221 Sentence denotes Lactoferrin expression in transgenic rice Ventrus Biosciences, New York City, New York, USA (184)
T208 27222-27280 Sentence denotes Transgenic cattle expressing human lactoferrin (185, 186)
T209 27281-27352 Sentence denotes Transgenic maize Meristem therapeutics, Clermont-Ferrand, France (184)
T210 27353-27413 Sentence denotes Lactoferrin supplementation in treatment of various diseases
T211 27414-27504 Sentence denotes Might be useful in treating sepsis or necrotizing enterocolitis in preterm neonates (184)
T212 27505-27538 Sentence denotes Support for vaginal health (187)
T213 27539-27736 Sentence denotes LF may play a protective role in host defense against SARS-CoV infection through binding to HSPGs and blocking the preliminary interaction between SARS-CoV and host cells (cell culture study) (99)
T214 27737-27910 Sentence denotes LF is a modulator of innate immune responses in the urinary tract and has potential application in novel therapeutic design for urinary tract infection (animal study) (188)
T215 27911-27993 Sentence denotes Possible therapy against Candida albicans in the oral cavity (a hypothesis) (189)
T216 27994-28062 Sentence denotes Protection against Chlamydia trachomatis (cell culture study) (190)
T217 28063-28130 Sentence denotes Treatment of taste and smell abnormalities after chemotherapy (52)
T218 28131-28204 Sentence denotes LF supplements and food with high levels of LF for oral health (99, 191)
T219 28205-28301 Sentence denotes LF treatment of black stain associated with of iron metabolism disorders with lactoferrin (192)
T220 28302-28468 Sentence denotes Aerosolized bovine LF counteracts infection, inflammation and iron dysbalance in a cystic fibrosis mouse model of Pseudomonas aeruginosa chronic lung infection (193)
T221 28469-28506 Sentence denotes LF inhalations for lung health (194)
T222 28507-28542 Sentence denotes LF for optimal skin moisture (195)
T223 28544-28555 Sentence denotes Conclusions
T224 28556-28668 Sentence denotes Lactoferrin clearly has immunological benefits, as well as having an important antibacterial and antiviral role.
T225 28669-28837 Sentence denotes Because it is known to interfere with some of the receptors used by coronaviruses, it may contribute usefully to the prevention and treatment of coronavirus infections.
T226 28838-28921 Sentence denotes Figure 6 shows a possible scheme on how LF might interfere with SARS-CoV-2 binding.
T227 28922-29049 Sentence denotes The binding of LF to HSPGs prevents the first contact between virus and host cells and thus prevents subsequent infection (99).
T228 29050-29105 Sentence denotes HSPGs themselves are not sufficient for SARS-CoV entry.
T229 29106-29206 Sentence denotes However, in SARS-CoV infections, the HSPGs play an important role in the process of cell entry (99).
T230 29207-29358 Sentence denotes The anchoring sites provided by HSPGs permit initial contact between the virus and host cells and the concentration of virus particles on cell surface.
T231 29359-29499 Sentence denotes SARS-CoV bound to HSPGs then rolls onto the cell membrane and scans for specific entry receptors, which leads to subsequent cell entry (99).
T232 29500-29689 Sentence denotes 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.
T233 29690-29858 Sentence denotes We suggest that this process might be the same for COVID-19 (see Figure 6 for a visual representation), thereby offering useful strategies for prevention and treatment.
T234 29859-29969 Sentence denotes Currently, there is also a renewed interest in ACE2 and HSPG blocking, as discussed in the introduction (5–8).
T235 29970-30124 Sentence denotes LF may therefore be an excellent supplement to take, not only as a contribution to prevention but perhaps as a therapy in the event COVID-19 is diagnosed.
T236 30125-30341 Sentence denotes Figure 6 Possible action of (1) lactoferrin by occupying binding sites of (2) SARS-CoV-2 that causes COVID-19. (3) Entry into host cells occur when SARS-CoV-2 first attaches to Heparan sulfate proteoglycans (HSPGs).
T237 30342-30989 Sentence denotes 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. (6) One of the characteristics of Lactoferrin, is that it attaches to HSPGs. (7) Currently we do not know if ACE2 is also a receptor for lactoferrin. (8) Lactoferrin may block the entry of SARS-CoV-2 into the host cell, by occupying HPSGs, thereby preventing SARS-CoV-2 initial attachment and accumulation on the host cell membrane.
T238 30990-31050 Sentence denotes COVID-19 infection template adjusted from www.biorender.com.
T239 31052-31079 Sentence denotes Data Availability Statement
T240 31080-31246 Sentence denotes The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
T241 31248-31261 Sentence denotes Author's Note
T242 31262-31364 Sentence denotes Another recent review (196) has also highlighted the potential utility of lactoferrin as an antiviral.
T243 31366-31386 Sentence denotes Author Contributions
T244 31387-31406 Sentence denotes EP wrote the paper.
T245 31407-31445 Sentence denotes DK edited and wrote part of the paper.
T246 31446-31494 Sentence denotes EH provided clinical input and edited the paper.
T247 31495-31540 Sentence denotes All authors approved submission of the paper.
T248 31542-31562 Sentence denotes Conflict of Interest
T249 31563-31735 Sentence denotes 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.
T250 31737-31745 Sentence denotes Funding.
T251 31746-31920 Sentence denotes We thank the Medical Research Council of South Africa (MRC) (Self-Initiated Research Program: A0X331) and the UK BBSRC (grant BB/L025752/1) for supporting this collaboration.
T252 31921-31934 Sentence denotes Abbreviations
T253 31935-31967 Sentence denotes LF Lactoferrin; lactotransferrin
T254 31968-32015 Sentence denotes SARS-CoV acute respiratory syndrome coronavirus
T255 32016-32057 Sentence denotes LRP-1/CD91 LDL receptor-related protein-1
T256 32058-32095 Sentence denotes TLR2 and 4 Toll-like receptor 2 and 4
T257 32096-32121 Sentence denotes CXCR4 cytokine receptor 4
T258 32122-32143 Sentence denotes GAG glycosaminoglycan
T259 32144-32168 Sentence denotes AP-1 activator protein 1
T260 32169-32188 Sentence denotes NF-κB NF-kappa beta
T261 32189-32221 Sentence denotes IRF Interferon regulatory factor
T262 32222-32259 Sentence denotes MAPK Mitogen-activated protein kinase
T263 32260-32294 Sentence denotes HSPG Heparan sulfate proteoglycans
T264 32295-32331 Sentence denotes ACE2 Angiotensin-converting enzyme 2
T265 32332-32346 Sentence denotes IL Interleukin
T266 32347-32390 Sentence denotes G-CSF Granulocyte colony-stimulating factor
T267 32391-32446 Sentence denotes GM-CSF Granulocyte-Macrophage Colony Stimulating Factor
T268 32447-32461 Sentence denotes IFN Interferon
T269 32462-32494 Sentence denotes TNFα Tumor necrosis factor alpha
T270 32495-32535 Sentence denotes IP10 Interferon gamma-induced protein 10
T271 32536-32575 Sentence denotes MCP1 Monocyte Chemoattractant Protein-1
T272 32576-32634 Sentence denotes (MIP1) A and B Macrophage inflammatory protein 1 (A and B)
T273 32635-32668 Sentence denotes LMWH Low molecular weight heparin
T274 32669-32694 Sentence denotes vWF von Willebrand Factor
T275 32695-32728 Sentence denotes PAD4 protein arginine deiminase 4
T276 32729-32765 Sentence denotes NETS Neutrophil extracellular traps.