An overview on in vitro and in vivo antiviral activity of lactoferrin: its efficacy against SARS-CoV-2 infection
Antimo Luigi Rosa, Antimo Cutone, Maria Pia Conte, Elena Campione, Luca Bianchi, Piera Valenti
BioMetals, doi:10.1007/s10534-022-00427-z
SARS-CoV-2. In vivo, Lf oral administration in early stage of SARS-CoV-2 infection counteracts COVID-19 pathogenesis. In particular, the effect of Lf on SARS-CoV-2 entry, inflammatory homeostasis, iron dysregulation, iron-proteins synthesis, reactive oxygen formation, oxidative stress, gut-lung axis regulation as well as on RNA negativization, and coagulation/fibrinolysis balance will be critically reviewed. Moreover, the molecular mechanisms underneath, including the Lf binding to HSPGs and spike glycoprotein, will be disclosed and discussed. Taken together, present data not only support the application of the oral administration of Lf alone in asymptomatic COVID-19 patients or as adjuvant of standard of care practice in symptomatic ones but also constitute the basis for enriching the limited literature on Lf effectiveness for COVID-19 treatment.
Keywords Lactoferrin • SARS-CoV-2 • COVID-19 • Inflammatory and iron homeostasis • Gut-lung axis • Coagulation and fibrinolysis
Lactoferrin and iron Lactoferrin (Lf), identified in 1939 in bovine milk and isolated in 1960 from both human (Johansson 1960; Montreuil et al. 1960 ) and bovine milk (Groves 1960), is constitutively synthesized by exocrine glands and secreted in human fluids. After induction,
Author contributions P.V.: conceptualization; L.R., A.C., and P.V.: writing: original
Declarations
Conflict of interest The authors declare no conflict of interest. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
References
Al-Samkari, Leaf, Dzik, Carlson, Fogerty et al., COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection, Blood,
doi:10.1182/blood.2020006520Algahtani, Elabbasy, Samak, Adeboye, Yusuf et al., The Prospect of lactoferrin use as adjunctive agent in management of SARS-CoV-2 patients: a randomized pilot study, Medicina (kaunas),
doi:10.3390/medicina57080842Ali, Hasan, Kow, Merchant, Lactoferrin reduces the risk of respiratory tract infections: a meta-analysis of randomized controlled trials, Clin Nutr ESPEN,
doi:10.1016/j.clnesp.2021.08.019Ammendolia, Agamennone, Pietrantoni, Lannutti, Siciliano et al., Bovine lactoferrin-derived peptides as novel broad-spectrum inhibitors of influenza virus, Pathog Glob Health,
doi:10.1179/2047773212Y.0000000004Bartley, Zhou, Kuchel, Weinstock, Haynes, Impact of age, caloric restriction, and influenza infection on mouse gut microbiome: an exploratory study of the role of age-related microbiome changes on influenza responses, Front Immunol,
doi:10.3389/fimmu.2017.01164Berlutti, Pantanella, Natalizi, Frioni, Paesano et al., Antiviral properties of lactoferrin-a natural immunity molecule, Molecules,
doi:10.3390/molecules16086992Bluard-Deconinck, Masson, Osinski, Heremans, Amino acid sequence of cysteic peptides of lactoferrin and demonstration of similarities between lactoferrin and transferrin, Biochim Biophys Acta,
doi:10.1016/0005-2795(74)90002-6Broz, Dixit, Inflammasomes: mechanism of assembly, regulation and signalling, Nat Rev Immunol,
doi:10.1038/nri.2016.58Budden, Gellatly, Wood, Cooper, Morrison et al., Emerging pathogenic links between microbiota and the gut-lung axis, Nat Rev Microbiol,
doi:10.1038/nrmicro.2016.142Campione, Cosio, Rosa, Lanna, Girolamo et al., Lactoferrin as protective natural barrier of respiratory and intestinal mucosa against coronavirus infection and inflammation, Int J Mol Sci,
doi:10.3390/ijms21144903Campione, Lanna, Cosio, Rosa, Conte et al., Lactoferrin against SARS-CoV-2 in vitro and in silico evidences, Front Pharmacol,
doi:10.3389/fphar.2021.666600Campione, Lanna, Cosio, Rosa, Conte et al., Lactoferrin as antiviral treatment in COVID-19 management: preliminary evidence, Int J Environ Res Public Health,
doi:10.3390/ijerph182010985Cheng, Li, Li, Liu, Yan et al., Ferritin in the coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis, J Clin Lab Anal,
doi:10.1002/jcla.23618Cui, Chen, Li, Liu, Wang, Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia, J Thromb Haemost,
doi:10.1111/jth.14830Cutone, Frioni, Berlutti, Valenti, Musci et al., Lactoferrin prevents LPS-induced decrease of the iron exporter ferroportin in human monocytes/macrophages, Biometals,
doi:10.1007/s10534-014-9742-7Cutone, Lepanto, Rosa, Scotti, Rossi et al., Aerosolized bovine lactoferrin counteracts infection, inflammation and iron dysbalance in a cystic fibrosis mouse model of Pseudomonas aeruginosa chronic lung infection, Int J Mol Sci,
doi:10.3390/ijms20092128Cutone, Rosa, Lepanto, Scotti, Berlutti et al., Lactoferrin efficiently counteracts the inflammation-induced changes of the iron homeostasis system in macrophages, Front Immunol,
doi:10.3389/fimmu.2017.00705Dai, Pan, Li, Liu, Zhang et al., The antimicrobial cathelicidin peptide hlF(1-11) attenuates alveolar macrophage pyroptosis induced by Acinetobacter baumannii in vivo, Exp Cell Res,
doi:10.1016/j.yexcr.2018.01.035Dai, Teng, Wu, The Antiviral roles of hydrogen sulfide by blocking the interaction between SARS-CoV-2 and its potential cell surface receptors, Oxid Med Cell Longev,
doi:10.1155/2021/7866992Denani, Real-Hohn, De Carvalho, Gomes, Gonçalves, Lactoferrin affects rhinovirus B-14 entry into H1-HeLa cells, Arch Virol,
doi:10.1007/s00705-021-04993-4Deriu, Boxx, He, Pan, Benavidez et al., Influenza virus affects intestinal microbiota and secondary Salmonella infection in the gut through Type I Interferons, PloS Pathog,
doi:10.1371/journal.ppat.1005572Di, Cutone, Polticelli, Rosa, Lepanto et al., The ferroportinceruloplasmin system and the mammalian iron homeostasis machine: regulatory pathways and the role of lactoferrin, Biometals,
doi:10.1007/s10534-018-0087-5Donovan, Lima, Pinkus, Pinkus, Zon et al., The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis, Cell Metab,
doi:10.1016/j.cmet.2005.01.003Ehsani, COVID-19 and iron dysregulation: distant sequence similarity between hepcidin and the novel coronavirus spike glycoprotein, Biol Direct,
doi:10.1186/s13062-020-00275-2Enaud, Prevel, Ciarlo, Beaufils, Wieërs et al., The gut-lung axis in health and respiratory diseases: a place for inter-organ and inter-kingdom crosstalks, Front Cell Infect Microbiol,
doi:10.3389/fcimb.2020.00009Fda, GRN 000465 Cow's Milk-Derived Lactoferrin
Fernandez-Musoles, Salom, Martínez-Maqueda, López-Díez, Recio et al., Antihypertensive effects of lactoferrin hydrolyzates: inhibition of angiotensin-and endothelin-converting enzymes, Food Chem,
doi:10.1016/j.foodchem.2012.12.049Figueroa-Lozano, Valk-Weeber, Van Leeuwen, Dijkhuizen, De Vos, Dietary N-Glycans from bovine lactoferrin and TLR modulation, Mol Nutr Food Res,
doi:10.1002/mnfr.201700389Fox, Akmatbekov, Harbert, Li, Brown et al., Pulmonary and cardiac pathology in African American patients with COVID-19: an Vol.: (0123456789) autopsy series from New Orleans, Lancet Respir Med,
doi:10.1016/S2213-2600(20)30243-5Frioni, Conte, Cutone, Longhi, Musci et al., Lactoferrin differently modulates the inflammatory response in epithelial models mimicking human inflammatory and infectious diseases, Biometals,
doi:10.1007/s10534-014-9740-9Fujihara, Hayashi, Lactoferrin inhibits herpes simplex virus type-1 (HSV-1) infection to mouse cornea, Arch Virol,
doi:10.1007/BF01322673Furlund, Kristoffersen, Devold, Vegarud, Jonassen, Bovine lactoferrin digested with human gastrointestinal enzymes inhibits replication of human echovirus 5 in cell culture, Nutr Res,
doi:10.1016/j.nutres.2012.06.006Furmanski, Li, Fortuna, Swamy, Das, Multiple molecular forms of human lactoferrin. Identification of a class of lactoferrins that possess ribonuclease activity and lack iron-binding capacity, J Exp Med,
doi:10.1084/jem.170.2.415Giobbe, Bonfante, Jones, Gagliano, Luni et al., SARS-CoV-2 infection and replication in human gastric organoids, Nat Commun,
doi:10.1038/s41467-021-26762-2Grier, Mcdavid, Wang, Qiu, Java et al., Neonatal gut and respiratory microbiota: coordinated development through time and space, Microbiome,
doi:10.1186/s40168-018-0566-5Groot, Geijtenbeek, Sanders, Baldwin, Sanchez-Hernandez et al., Lactoferrin prevents dendritic cell-mediated human immunodeficiency virus type 1 transmission by blocking the DC-SIGN-gp120 interaction, J Virol,
doi:10.1128/JVI.79.5.3009-3015.2005Groves, Cuthbertson, James, Moffatt, Cox et al., Respiratory disease following viral lung infection alters the murine gut microbiota, Front Immunol,
doi:10.3389/fimmu.2018.00182Groves, The isolation of a red protein from milk, J Am Chem Soc
Gualdi, Mertz, Gomez, Ramilo, Wittke et al., Lack of effect of bovine lactoferrin in respiratory syncytial virus replication and clinical disease severity in the mouse model, Antiviral Res,
doi:10.1016/j.antiviral.2013.05.013Hanada, Pirzadeh, Carver, Deng, Respiratory viral infection-induced microbiome alterations and secondary bacterial pneumonia, Front Immunol,
doi:10.3389/fimmu.2018.02640Hatmal, Alshaer, Al-Hatamleh, Hatmal, Smadi et al., Comprehensive structural and molecular comparison of spike proteins of SARS-CoV-2, SARS-CoV and MERS-CoV, and their interactions with ACE2, Cells,
doi:10.3390/cells9122638Hirashima, Orito, Ohba, Kondo, Sakamoto et al., A randomized controlled trial of consensus interferon with or without lactoferrin for chronic hepatitis C patients with genotype 1b and high viral load, Hepatol Res,
doi:10.1016/j.hepres.2004.01.002Hu, Meng, Zhang, Xiang, Wang, The in vitro antiviral activity of lactoferrin against common human coronaviruses and SARS-CoV-2 is mediated by targeting the heparan sulfate co-receptor, Emerg Microbes Infect,
doi:10.1080/22221751.2021.1888660Hunter, Fulton, Ganz, Vogel, The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis, J Biol Chem,
doi:10.1074/jbc.M205305200Hussain, Cher, Abid, Abid, Role of gut microbiome in COVID-19: an insight into pathogenesis and therapeutic potential, Front Immunol,
doi:10.3389/fimmu.2021.765965Ichinohe, Pang, Kumamoto, Peaper, Ho et al., Microbiota regulates immune defense against respiratory tract Influenza A virus infection, Proc Natl Acad Sci U S A,
doi:10.1073/pnas.1019378108Ishibashi, Takeda, Tsukidate, Miyazaki, Ohira et al., Randomized placebo-controlled trial of interferon alpha-2b plus ribavirin with and without lactoferrin for chronic hepatitis C, Hepatol Res,
doi:10.1016/j.hepres.2005.03.018Johansson, Isolation of an iron-containing red protein from human milk, Acta Chem Scand
Kalashnyk, Petrova, Lykhmus, Mikhalovska, Mikhalovsky et al., Expression, function and cooperating partners of protease-activated receptor type 3 in vascular endothelial cells and B lymphocytes studied with specific monoclonal antibody, Mol Immunol,
doi:10.1016/j.molimm.2012.12.021Ke, Oton, Qu, Cortese, Zila et al., Structures and distributions of SARS-CoV-2 spike proteins on intact virions, Nature,
doi:10.1038/s41586-020-2665-2Kell, Heyden, Pretorius, The Biology of lactoferrin, an iron-binding protein that can help defend against viruses and bacteria, Front Immunol,
doi:10.3389/fimmu.2020.01221Klok, Kruip, Van Der Meer, Arbous, Gommers et al., Incidence of thrombotic complications in critically ill ICU patients with COVID-19, Thromb Res,
doi:10.1016/j.thromres.2020.04.013Krause, Neitz, Magert, Schulz, Forssmann et al., LEAP-1, a novel highly disulfidebonded human peptide, exhibits antimicrobial activity, FEBS Lett,
doi:10.1016/s0014-5793(00)01920-7Kruzel, Actor, Boldogh, Zimecki, Lactoferrin in health and disease, Postepy Hig Med Dosw
Kuhara, Yamauchi, Tamura, Okamura, Oral administration of lactoferrin increases NK cell activity in mice via increased production of IL-18 and type I IFN in the small intestine, J Interferon Cytokine Res,
doi:10.1089/jir.2006.26.489Lang, Yang, Deng, Liu, Yang et al., Inhibition of SARS pseudovirus cell entry by lactoferrin binding to heparan sulfate proteoglycans, PLoS ONE,
doi:10.1371/journal.pone.0023710Latz, Xiao, Stutz, Activation and regulation of the inflammasomes, Nat Rev Immunol,
doi:10.1038/nri3452Lee, Peng, Gelbart, Wang, Beutler, Regulation of hepcidin transcription by interleukin-1 and interleukin-6, Proc Natl Acad Sci,
doi:10.1073/pnas.0409808102Legrand, Elass, Carpentier, Mazurier, Lactoferrin: a modulator of immune and inflammatory responses, Cell Mol Life Sci,
doi:10.1007/s00018-005-5370-2Lepanto, Rosa, Cutone, Conte, Paesano et al., Efficacy of lactoferrin oral administration in the treatment of anemia and anemia of inflammation in pregnant and non-pregnant women: an interventional study, Front Immunol,
doi:10.3389/fimmu.2018.02123Leveugle, Mazurier, Legrand, Mazurier, Montreuil et al., Lactotransferrin binding to its platelet receptor inhibits platelet aggregation, Eur J Biochem,
doi:10.1111/j.1432-1033.1993.tb17871.xLin, Chu, Chiu, Lactoferrin inhibits enterovirus 71 infection of human embryonal rhabdomyosarcoma cells in vitro, J Infect Dis,
doi:10.1086/343809Liu, Philippou, Kolokotroni, Siakallis, Rahima et al., Gut and airway microbiota and their role in COVID-19 infection and pathogenesis: a scoping review, Infection,
doi:10.1007/s15010-021-01715-5Longstaff, Kolev, Basic mechanisms and regulation of fibrinolysis, J Thromb Haemost,
doi:10.1111/jth.12935Lu, Hangoc, Oliff, Chen, Shen et al., Protective influence of lactoferrin on mice infected with the polycythemia-inducing strain of Friend virus complex, Cancer Res
Mancinelli, Rosa, Cutone, Lepanto, Franchitto et al., Viral hepatitis and iron dysregulation: molecular pathways and the role of lactoferrin, Molecules,
doi:10.3390/molecules25081997Mangan, Olhava, Roush, Seidel, Glick et al., Targeting the NLRP3 inflammasome in inflammatory diseases, Nat Rev Drug Discov,
doi:10.1038/nrd.2018.149Marchetti, Ammendolia, Superti, Glycosaminoglycans are not indispensable for the anti-herpes simplex virus type 2 activity of lactoferrin, Biochimie,
doi:10.1016/j.biochi.2008.04.015Marchetti, Longhi, Conte, Pisani, Valenti et al., Lactoferrin inhibits herpes simplex virus type 1 adsorption to Vero cells, Antiviral Res,
doi:10.1016/0166-3542(95)00840-3Marchetti, Pisani, Antonini, Valenti, Seganti et al., Metal complexes of bovine lactoferrin inhibit in vitro replication of herpes simplex virus type 1 and 2, Biometals,
doi:10.1023/a:1009217709851Marchetti, Superti, Ammendolia, Rossi, Valenti et al., Inhibition of poliovirus type 1 infection by iron-, manganese-and zinc-saturated lactoferrin, Med Microbiol Immunol,
doi:10.1007/s004300050093Miotto, Rienzo, Bò, Boffi, Ruocco et al., Molecular mechanisms behind anti SARS-CoV-2 action of lactoferrin, Front Mol Biosci,
doi:10.3389/fmolb.2021.607443Mirabelli, Wotring, Zhang, Mccarty, Fursmidt et al., Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19, Proc Natl Acad Sci U S A,
doi:10.1073/pnas.2105815118Montreuil, Tonnelat, Mullet, Preparation and properties of lactosiderophilin (lactotransferrin) of human milk, Biochim Biophys Acta
Motoki, Mizuki, Tsukahara, Miyakawa, Kubo et al., Effects of lactoferrin-fortified formula on acute gastrointestinal symptoms in children aged 12-32 months: a randomized, double-blind, Placebo-Controlled Trial Front Pediatr,
doi:10.3389/fped.2020.00233Nai, Lorè, Pagani, Lorenzo, Modica et al., Hepcidin levels predict Covid-19 severity and mortality in a cohort of hospitalized Italian patients, Am J Hematol,
doi:10.1002/ajh.26027Nemeth, Rivera, Gabayan, Keller, Taudorf et al., IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin, J Clin Investig,
doi:10.1172/JCI20945Oda, Wakabayashi, Tanaka, Yamauchi, Sugita et al., Effects of lactoferrin on infectious diseases in Japanese summer: a randomized, double-blinded, placebo-controlled trial, J Microbiol Immunol Infect,
doi:10.1016/j.jmii.2020.02.010Paesano, Berlutti, Pietropaoli, Goolsbee, Pacifici et al., Lactoferrin efficacy versus ferrous sulfate in curing iron disorders in pregnant and non-pregnant women, Int J Immunopathol Pharmacol,
doi:10.1177/039463201002300220Paesano, Natalizi, Berlutti, Valenti, Body iron delocalization: the serious drawback in iron disorders in both developing and developed countries, Pathog Glob Health,
doi:10.1179/2047773212Y.0000000043Pan, Shen, Yu, Ge, Chen et al., SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation, J Biol Chem,
doi:10.1074/jbc.M008922200Pan, Zhang, Liu, Wang, Lao et al., Dengue virus M protein promotes NLRP3 Inflammasome activation to induce vascular leakage in mice, J Virol,
doi:10.1128/JVI.00996-19Perricone, Bartoloni, Bursi, Cafaro, Guidelli et al., COVID-19 as part of the hyperferritinemic syndromes: the role of iron depletion therapy, Immunol Res,
doi:10.1007/s12026-020-09145-5Pietrantoni, Ammendolia, Superti, Bovine lactoferrin: involvement of metal saturation and carbohydrates in the inhibition of influenza virus infection, Biochem Cell Biol,
doi:10.1139/o11-072Pietrantoni, Biase, Tinari, Marchetti, Valenti et al., Bovine lactoferrin inhibits adenovirus infection by interacting with viral structural polypeptides, Antimicrob Agents Chemother,
doi:10.1128/AAC.47.8.2688-2691.2003Pietrantoni, Dofrelli, Tinari, Ammendolia, Puzelli et al., Bovine lactoferrin inhibits influenza A virus induced programmed cell death in vitro, Biometals,
doi:10.1007/s10534-010-9323-3Puddu, Borghi, Gessani, Valenti, Belardelli et al., Antiviral effect of bovine lactoferrin saturated with metal ions on early steps of human immunodeficiency virus type 1 infection, Int J Biochem Cell Biol,
doi:10.1016/s1357-2725(98)00066-1Puddu, Latorre, Carollo, Catizone, Ricci et al., Bovine lactoferrin counteracts toll-like receptor mediated activation signals in antigen presenting cells, PLoS ONE,
doi:10.1371/journal.pone.0022504Pérez-Cano, Marín-Gallén, Castell, Rodríguez-Palmero, Rivero et al., Supplementing suckling rats with whey protein concentrate modulates the immune response and ameliorates rat rotavirus-induced diarrhea, Nutr,
doi:10.3945/jn.108.093856Qian, Jollès, Migliore-Samour, Fiat, Isolation and characterization of sheep lactoferrin, an inhibitor of platelet aggregation and comparison with human lactoferrin, Biochim Biophys Acta,
doi:10.1016/0304-4165(94)00126-iQiao, Sugianto, Fung, Del-Castillo-Rueda, Moran-Jimenez et al., Hepcidin-induced endocytosis of ferroportin is dependent Vol:. (1234567890) on ferroportin ubiquitination, Cell Metab,
doi:10.1016/j.cmet.2012.03.018Rosa, Cutone, Lepanto, Paesano, Valenti, Lactoferrin: a natural glycoprotein involved in iron and inflammatory homeostasis, Int J Mol Sci,
doi:10.3390/ijms18091985Rosa, Tripepi, Naldi, Aimati, Santangeli et al., Ambulatory COVID-19 patients treated with lactoferrin as a supplementary antiviral agent: a preliminary study, J Clin Med,
doi:10.3390/jcm10184276Sano, Nagai, Tsutsumi, Kuroki, Lactoferrin and surfactant protein a exhibit distinct binding specificity to F protein and differently modulate respiratory syncytial virus infection, Eur J Immunol,
doi:10.1002/eji.200324218Serrano, Kochergina, Albors, Diaz, Oroval et al., Liposomal lactoferrin as potential preventative and cure for COVID-19, Int J Res Health Sci,
doi:10.5530/ijrhs.8.1.3Sherman, Pritzl, Xia, Miller, Zaghouani et al., Lactoferrin acts as an adjuvant during influenza vaccination of neonatal mice, Biochem Biophys Res Commun,
doi:10.1016/j.bbrc.2015.10.067Shimizu, Matsuzawa, Okada, Tazume, Dosako et al., Lactoferrinmediated protection of the host from murine cytomegalovirus infection by a T-cell-dependent augmentation of natural killer cell activity, Arch Virol,
doi:10.1007/BF01718201Shin, Wakabayashi, Yamauchi, Teraguchi, Tamura et al., Effects of orally administered bovine lactoferrin and lactoperoxidase on influenza virus infection in mice, J Med Microbiol,
doi:10.1099/jmm.0.46018-0Sienkiewicz, Jaśkiewicz, Tarasiuk, Fichna, Lactoferrin: an overview of its main functions, immunomodulatory and antimicrobial role, and clinical significance, Crit Rev Food Sci Nutr,
doi:10.1080/10408398.2021.1895063Skendros, Mitsios, Chrysanthopoulou, Mastellos, Metallidis et al., Complement and tissue factor-enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis, J Clin Invest,
doi:10.1172/JCI141374Spik, Coddeville, Mazurier, Bourne, Cambillaut et al., Primary and three-dimensional structure of lactotransferrin (lactoferrin) glycans, Adv Exp Med Biol,
doi:10.1007/978-1-4615-2548-6_3Stefanescu, Hétu, Slaughter, Shea, Shetty, A pilot study of Biotene OralBalance® gel for oral care in mechanically ventilated preterm neonates, Contemp Clin Trials,
doi:10.1016/j.cct.2013.03.010Superti, Ammendolia, Valenti, Seganti, Antirotaviral activity of milk proteins: lactoferrin prevents rotavirus infection in the enterocyte-like cell line HT-29, Med Microbiol Immunol,
doi:10.1007/s004300050049Superti, Siciliano, Rega, Giansanti, Valenti et al., Involvement of bovine lactoferrin metal saturation, sialic acid and protein fragments in the inhibition of rotavirus infection, Biochim Biophys Acta,
doi:10.1016/s0304-4165(01)00178-7Swart, Kuipers, Smit, Pauwels, Debéthune et al., Antiviral effects of milk proteins: acylation results in polyanionic compounds with potent activity against human immunodeficiency virus types 1 and 2 in vitro, AIDS Res Hum Retroviruses,
doi:10.1089/aid.1996.12.769Taha, Mehrez, Sitohy, Dawood, Hamid et al., Effectiveness of esterified whey proteins fractions against Egyptian Lethal Avian Influenza A (H5N1), Virol J,
doi:10.1186/1743-422X-7-330Tanaka, Ikeda, Nozaki, Kato, Tsuda et al., Lactoferrin inhibits hepatitis C virus viremia in patients with chronic hepatitis C: a pilot study, Jpn J Cancer Res,
doi:10.1111/j.1349-7006.1999.tb00756.xTian, Hu, Niu, Liu, Xu et al., Pulmonary pathology of early-phase 2019 novel Coronavirus (COVID-19) Pneumonia in two patients with lung cancer, J Thorac Oncol,
doi:10.1016/j.jtho.2020.02.010Tinari, Pietrantoni, Ammendolia, Valenti, Superti, Inhibitory activity of bovine lactoferrin against echovirus induced programmed cell death in vitro, Int J Antimicrob Agents,
doi:10.1016/j.ijantimicag.2005.02.011Toldo, Bussani, Nuzzi, Bonaventura, Mauro et al., Inflammasome formation in the lungs of patients with fatal COVID-19, Inflamm Res,
doi:10.1007/s00011-020-01413-2Ueno, Sato, Yamamoto, Tanaka, Ohkawa et al., Randomized, double-blind, placebo-controlled trial of bovine lactoferrin in patients with chronic
Valenti, Rosa, Capobianco, Lepanto, Schiavi et al., Role of Lactobacilli and Lactoferrin in the Mucosal Cervicovaginal Defense, Front Immunol,
doi:10.3389/fimmu.2018.00376Van Splunter, Perdijk, Fick-Brinkhof, Feitsma, Vollenbroek et al., Bovine lactoferrin enhances TLR7-mediated responses in plasmacytoid dendritic cells in elderly women: results from a nutritional intervention study with bovine lactoferrin, GOS Vitamin d Front Immunol,
doi:10.3389/fimmu.2018.02677Van Veen, Geerts, Van Berkel, Nuijens, The role of N-linked glycosylation in the protection of human and bovine lactoferrin against tryptic proteolysis, Eur J Biochem,
doi:10.1111/j.1432-1033.2003.03965.xVerga Falzacappa, Spasic, Kessler, Stolte, Hentze et al., STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation, Blood,
doi:10.1182/blood-2006-07-033969Vitetta, Coulson, Beck, Gramotnev, Du et al., The clinical efficacy of a bovine lactoferrin/whey protein Ig-rich fraction (Lf/IgF) for the common cold: a double blind randomized study, Complement Ther Med,
doi:10.1016/j.ctim.2012.12.006Vlahakos, Marathias, Arkadopoulos, Vlahakos, Hyperferritinemia in patients with COVID-19: an opportunity for iron chelation?, Artif Organs,
doi:10.1111/aor.13812Wakabayashi, Kurokawa, Shin, Teraguchi, Tamura et al., Oral lactoferrin prevents body weight loss and increases cytokine responses during herpes simplex virus type 1 infection of mice, Biosci Biotechnol Biochem,
doi:10.1271/bbb.68.537Wan, Du, Hong, Chen, Que et al., Neurological complications and infection mechanism of SARS-COV-2, Signal Transduct Target Ther,
doi:10.1038/s41392-021-00818-7Wang, Jiang, Yan, Gong, Han et al., RNA viruses promote activation of the NLRP3 inflammasome through a RIP1-RIP3-DRP1 signaling pathway, Nat Immunol,
doi:10.1038/ni.3015Wang, Li, Wei, Lian, Sun et al., Respiratory influenza virus infection induces intestinal immune injury via microbiota-mediated Th17 cell-dependent inflammation, J Exp Med,
doi:10.1084/jem.20140625Wang, Yue, Dang, Yang, Chen et al., Role of sialylated glycans on bovine lactoferrin against influenza virus, Glycoconjugate J,
doi:10.1007/s10719-021-10029-5Welsh, Hwang, Boyd, Kruzel, Hunter et al., Influence of oral lactoferrin on Mycobacterium tuberculosis induced immunopathology, Tuberculosis,
doi:10.1016/j.tube.2011.10.019Wisgrill, Wessely, Spittler, Förster-Waldl, Berger et al., Human lactoferrin attenuates the proinflammatory response of neonatal monocyte-derived macrophages, Clin Exp Immunol,
doi:10.1111/cei.13108Wu, Monroe, Church, Characterization of the glycosaminoglycan-binding region of lactoferrin, Arch Biochem Biophys,
doi:10.1006/abbi.1995.1139Xu, Fan, Liu, Cheng, Tu et al., Novel anticoagulant peptide from lactoferrin binding thrombin at the active site and Exosite-I, J Agric Food Chem,
doi:10.1021/acs.jafc.9b08094Xu, Shi, Wang, Zhang, Huang et al., Pathological findings of COVID-19 associated with acute respiratory distress syndrome, Lancet Respir Med,
doi:10.1016/S2213-2600(20)30076-XYamamoto, Ura, Tanemura, Koyama, Takano et al., Inhibitory effect of bovine lactoferrin on human parainfluenza virus type 2 infection, J Health Sci,
doi:10.1248/jhs.56.613Yen, Chiu, Huang, Lin, Effects of lactoferrin-containing formula in the prevention of enterovirus and rotavirus infection and impact on serum cytokine levels: a randomized trial, Chang Gung Med J
Yildiz, Mazel-Sanchez, Kandasamy, Manicassamy, Schmolke, Influenza A virus infection impacts systemic microbiota dynamics and causes quantitative enteric dysbiosis, Microbiome,
doi:10.1186/s40168-017-0386-zZhu, Zhang, Li, Yang, Song et al., China Novel Coronavirus Investigating and Research Team (2020) A novel coronavirus from patients with pneumonia in China, 2019, N Engl J Med,
doi:10.1056/NEJMoa2001017Zumerle, Mathieu, Delga, Heinis, Viatte et al., Targeted disruption of hepcidin in the liver recapitulates the hemochromatotic phenotype, Blood,
doi:10.1182/blood-2014-01-550467Zuo, Warnock, Harbaugh, Yalavarthi, Gockman et al., Plasma tissue plasminogen activator and plasminogen activator inhibitor-1 in hospitalized COVID-19 patients, Sci Rep,
doi:10.1038/s41598-020-80010-zZwirzitz, Reiter, Skrabana, Ohradanova-Repic, Majdic et al., Lactoferrin is a natural inhibitor of plasminogen activation, J Biol Chem,
doi:10.1074/jbc.RA118.003145
