Lactoferrin as potential preventative and adjunct treatment for COVID-19
Raymond Chang, Tzi Bun Ng, Wei-Zen Sun
International Journal of Antimicrobial Agents, doi:10.1016/j.ijantimicag.2020.106118
The coronavirus disease 2019 (COVID-19) pandemic is rapidly advancing across the globe despite drastic public and personal health measures. Antivirals and nutritional supplements have been proposed as potentially useful against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the novel coronavirus that causes COVID-19, but few have been clinically established. Lactoferrin (Lf) is a naturally occurring, non-toxic glycoprotein that is orally available as a nutritional supplement and has established in vitro antiviral efficacy against a wide range of viruses, including SARS-CoV, a closely related coronavirus to SARS-CoV-2. Furthermore, Lf possesses unique immunomodulatory and anti-inflammatory effects that may be especially relevant to the pathophysiology of severe COVID-19 cases. Here we review the underlying biological mechanisms of Lf as an antiviral and immune regulator, and propose its unique potential as a preventative and adjunct treatment for COVID-19. We hope that further research and development of Lf nutritional supplementation would establish its role for COVID-19.
Competing interests: None declared. Ethical approval: Not required.
References
Andersen, Jenssen, Sandvik, Gutteberg, Anti-HSV activity of lactoferrin and lactoferricin is dependent on the presence of heparan sulphate at the cell surface, J Med Virol,
doi:10.1002/jmv.20171Baveye, Elass, Mazurier, Spik, Legrand, Lactoferrin: a multifunctional glycoprotein involved in the modulation of the inflammatory process, Clin Chem Lab Med,
doi:10.1515/CCLM.1999.049Behrens, Koretzky, Review: cytokine storm syndrome: looking toward the precision medicine era, Arthritis Rheumatol,
doi:10.1002/art.40071Bone, Balk, Cerra, Dellinger, Fein et al., Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis,
doi:10.1378/chest.101.6.1644Bruni, Capucchio, Biasibetti, Pessione, Cirrincione et al., Antimicrobial activity of lactoferrin-related peptides and applications in human and veterinary medicine, Molecules,
doi:10.3390/molecules21060752Calina, Docea, Petrakis, Egorov, Ishmukhametov et al., Towards effective COVID-19 vaccines: updates, perspectives and challenges (review), Int J Mol Med,
doi:10.3892/ijmm.2020.4596Chen, Liu, Guo, Emerging coronaviruses: genome structure, replication, and pathogenesis, J Med Virol,
doi:10.1002/jmv.25681Egashira, Takayanagi, Moriuchi, Moriuchi, Does daily intake of bovine lactoferrin-containing products ameliorate rotaviral gastroenteritis, Acta Paediatr,
doi:10.1111/j.1651-2227.2007.00393.xFung, Yuen, Ye, Chan, Jin, A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: lessons from other pathogenic viruses, Emerg Microbes Infect,
doi:10.1080/22221751.2020.1736644Guntupalli, Dean, Morris, Bandi, Margolis et al., A phase 2 randomized, double-blind, placebo-controlled study of the safety and efficacy of talactoferrin in patients with severe sepsis, Crit Care Med,
doi:10.1097/CCM.0b013e3182741551Hoffmann, Kleine-Weber, Schroeder, Krüger, Herrler et al., SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor, Cell,
doi:10.1016/j.cell.2020.02.052Hong, Wang, Chung, Chen, Clinical characteristics of novel coronavirus disease 2019 (COVID-19) in newborns, infants and children, Pediatr Neonatol,
doi:10.1016/j.pedneo.2020.03.001Ishikado, Imanaka, Takeuchi, Harada, Makino, Liposomalization of lactoferrin enhanced it's anti-inflammatory effects via oral administration, Biol Pharm Bull,
doi:10.1248/bpb.28.1717Kaito, Iwasa, Fujita, Kobayashi, Kojima et al., Effect of lactoferrin in patients with chronic hepatitis C: combination therapy with interferon and ribavirin, J Gastroenterol Hepatol,
doi:10.1111/j.1440-1746.2007.04858.xKruzel, Actor, Radak, Bacsi, Saavedra-Molina et al., Lactoferrin decreases LPS-induced mitochondrial dysfunction in cultured cells and in animal endotoxemia model, Innate Immun,
doi:10.1177/1753425909105317Kruzel, Harari, Chen, Castro, Lactoferrin protects gut mucosal integrity during endotoxemia induced by lipopolysaccharide in mice, Inflammation,
doi:10.1023/a:1006935908960Lang, 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.0023710Legrand, Elass, Carpentier, Mazurier, Interactions of lactoferrin with cells involved in immune function, Biochem Cell Biol,
doi:10.1139/o06-045Levay, Viljoen, Lactoferrin: a general review, Haematologica
Lu, Hangoc, Oliff, Chen, Shen et al., Protective influence of lactoferrin on mice infected with the polycythemia-inducing strain of Friend virus complex, Cancer Res
Marchetti, Superti, Ammendolia, Rossi, Valenti et al., Inhibition of poliovirus type 1 infection by iron-, manganese-and zincsaturated lactoferrin, Med Microbiol Immunol,
doi:10.1007/s004300050093Mehta, Mcauley, Brown, Sanchez, Tattersall et al., Across Speciality Collaboration. COVID-19: consider cytokine storm syndromes and immunosuppression, Lancet,
doi:10.1016/S0140-6736(20)30628-0Milewska, Zarebski, Nowak, Stozek, Potempa et al., Human coronavirus NL63 utilizes heparan sulfate proteoglycans for attachment to target cells, J Virol,
doi:10.1128/jvi.02078-14Nozaki, Ikeda, Naganuma, Nakamura, Inudoh et al., Identification of a lactoferrin-derived peptide possessing binding activity to hepatitis C virus E2 envelope protein, J Biol Chem,
doi:10.1074/jbc.M207879200Oda, Nakano, Wakabayashi, Yamauchi, Toida et al., Questionnaire survey on the subjective effects of a lactoferrin supplement, J Jpn Soc Complement Altern Med,
doi:10.1625/jcam.9.121Puddu, 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)00066-1Razak, Hussain, Lactoferrin supplementation to prevent late-onset sepsis in preterm infants: a meta-analysis, Am J Perinatol,
doi:10.1055/s-0039-1696676Rosa, Cutone, Lepanto, Paesano, Valenti, Lactoferrin: a natural glycoprotein involved in iron and inflammatory homeostasis, Int J Mol Sci,
doi:10.3390/ijms18091985Serrano, Kochergina, Albors, Diaz, Oroval et al., Liposomal lactoferrin as potential prevention and cure for COVID-19, Int J Res Health Sci,
doi:10.5530/ijrhs.8.1.3Siqueiros-Cendón, Arévalo-Gallegos, Iglesias-Figueroa, García-Montoya, Salazar-Martínez et al., Immunomodulatory effects of lactoferrin, Acta Pharmacol Sin,
doi:10.1038/aps.2013.200Sorensen, Sorensen, The proteins in whey, C R Trav Lab Carlsb Ser Chim
Vincent, Marshall, Dellinger, Simonson, Guntupalli et al., Talactoferrin in severe sepsis: results from the phase II/III Oral tAlactoferrin in Severe sepsis Trial, Crit Care Med,
doi:10.1097/CCM.0000000000001090Vitetta, 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.2012.12.006Wei, Yuan, Liu, Fu, Yu et al., Novel coronavirus infection in hospitalized infants under 1 year of age in China, JAMA,
doi:10.1001/jama.2020.2131Zhang, Liu, Potential interventions for novel coronavirus in China: a systematic review, J Med Virol,
doi:10.1002/jmv.25707Zhu, Zhang, Li, Yang, Song, A novel coronavirus from patients with pneumonia in China, 2019, N Engl J Med,
doi:10.1056/NEJMoa2001017Zimecki, Właszczyk, Zagulski, Kübler, Lactoferrin lowers serum interleukin 6 and tumor necrosis factor alpha levels in mice subjected to surgery, Arch Immunol Ther Exp (Warsz)
