Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of novel coronavirus disease 2019 (COVID-19), a major cause of atypical pneumonia worldwide. Elderly individuals and those with underlying illnesses, such as cardiovascular and pulmonary diseases, are at a high risk of experiencing severe symptoms and have high mortality rates. There is therefore a major need to develop additional vaccines, effective treatments, and complementary drugs to control this infection. Lactoferrin (LF), a naturally-occurring glycoprotein, is bioactive against viruses and other pathogens. LF has a unique immunomodulatory function and is indispensable for immunity in infants. It is thought to contribute to biological defense in individuals across all generations, not only infants. LF inhibits viral adhesion to host cell surfaces through ionic binding to glycosaminoglycans and/or specific binding to viral structures. Purified LF is cost-effective and orally available as a dietary supplement. Here, we review studies on the protective role of LF against common viral infections. Based on this review, we propose that LF can be a possible prophylactic or therapeutic agent for COVID-19 disease.

1. [1] Y. Wang et al., “Lactoferrin for the treatment of COVID-19 (Review),” Experimental and Therapeutic Medicine, Vol.20, No.6, 272, 2020.
2. [2] V. Giustino et al., “Physical activity levels and related energy expenditure during COVID-19 quarantine among the Sicilian active population: A cross-sectional online survey study,” Sustainability, Vol.12, No.11, 4356, 2020.
3. [3] A. Paoli and G. Musumeci, “Elite athletes and COVID-19 lockdown: Future health concerns for an entire sector,” J. of Functional Morphology and Kinesiology, Vol.5, No.2, 30, 2020.
4. [4] N. H. El-Subbagh et al., “Characteristic features of coronavirus disease-2019 (COVID-19) pandemic: Attention to the management and control in Egypt,” J. Disaster Res., Vol.16, No.1, pp. 70-83, 2021.
5. [5] N. Nakanishi and Y. Iijima, “The novel coronavirus pandemic and the state of the epidemic in Kobe, Japan,” J. Disaster Res., Vol.16, No.1, pp. 84-87, 2021.
6. [6] N. Leelawat et al., “Comparison of the initial overseas evacuation operations due to COVID-19: A focus on Asian countries,” J. Disaster Res., Vol.16, No.7, pp. 1137-1146, 2021.
7. [7] N. Chen et al., “Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study,” The Lancet, Vol.395, No.10223, pp. 507-513, 2020.
8. [8] D. Petrakis et al., “Obesity – A risk factor for increased COVID-19 prevalence, severity and lethality (Review),” Molecular Medicine Reports, Vol.22, No.1, pp. 9-19, 2020.
9. [9] H. Wakabayashi, H. Oda, K. Yamauchi, and F. Abe, “Lactoferrin for prevention of common viral infections,” J. of Infection and Chemotherapy, Vol.20, No.11, pp. 666-671, 2014.
10. [10] D. B. Kell, E. L. Heyden, and E. Pretorius, “The biology of lactoferrin, an iron-binding protein that can help defend against viruses and bacteria,” Frontiers in Immunology, Vol.11, 1221, 2020.
11. [11] D. Legrand, E. Elass, M. Carpentier, and J. Mazurier, “Interactions of lactoferrin with cells involved in immune function,” Biochemistry and Cell Biology, Vol.84, No.3, pp. 282-290, 2006.
12. [12] H. Wakabayashi, K. Yamauchi, and F. Abe, “Quality control of commercial bovine lactoferrin,” BioMetals, Vol.31, No.3, pp. 313-319, 2018.
13. [13] M. Yu et al., “Elucidating the interactions between heparin/heparan sulfate and SARS-CoV-2-related proteins—An important strategy for developing novel therapeutics for the COVID-19 pandemic,” Frontiers in Molecular Biosciences, Vol.7, 628551, 2021.
14. [14] M. Scudellari, “How the coronavirus infects cells – and why Delta is so dangerous,” Nature, Vol.595, pp. 640-644, 2021.
15. [15] C. Guney and F. Akar, “Epithelial and endothelial expressions of ACE2: SARS-CoV-2 entry routes,” J. of Pharmacy & Pharmaceutical Sciences, Vol.24, pp. 84-93, 2021.
16. [16] J. Koch et al., “TMPRSS2 expression dictates the entry route used by SARS-CoV-2 to infect host cells,” The EMBO J., Vol.40, No.16, e107821, 2021.
17. [17] A. Pišlar et al., “The role of cysteine peptidases in coronavirus cell entry and replication: The therapeutic potential of cathepsin inhibitors,” PLOS Pathogens, Vol.16, No.11, e1009013, 2020.
18. [18] N. Huang et al., “SARS-CoV-2 infection of the oral cavity and saliva,” Nature Medicine, Vol.27, No.5, pp. 892-903, 2021.
19. [19] G. Descamps et al., “ACE2 protein landscape in the head and neck region: The conundrum of SARS-CoV-2 infection,” Biology, Vol.9, No.8, 235, 2020.
20. [20] S. Matsuyama et al., “Enhanced isolation of SARS-CoV-2 by TMPRSS2-expressing cells,” Proc. of the National Academy of Sciences, Vol.117, No.13, pp. 7001-7003, 2020.
21. [21] D. Zarzosa-Moreno et al., “Lactoferrin and its derived peptides: An alternative for combating virulence mechanisms developed by pathogens,” Molecules, Vol.25, No.24, 5763, 2020.
22. [22] I. G. Goodfellow, A. B. Sioofy, R. M. Powell, and D. J. Evans, “Echoviruses bind heparan sulfate at the cell surface,” J. of Virology, Vol.75, No.10, pp. 4918-4921, 2001.
23. [23] J. Lang et al., “Inhibition of SARS pseudovirus cell entry by lactoferrin binding to heparan sulfate proteoglycans,” PLOS ONE, Vol.6, No.8, e23710, 2011.
24. [24] Y. Hu, X. Meng, F. Zhang, Y. Xiang, and J. 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,” Emerging Microbes & Infections, Vol.10, No.1, pp. 317-330, 2021.
25. [25] V. Cagno, E. D. Tseligka, S. T. Jones, and C. Tapparel, “Heparan sulfate proteoglycans and viral attachment: True receptors or adaptation bias?,” Viruses, Vol.11, No.7, 596, 2019.
26. [26] C. B. Denani, A. Real-Hohn, C. A. M. de Carvalho, A. M. D. O. Gomes, and R. B. Gonçalves, “Lactoferrin affects rhinovirus B-14 entry into H1-HeLa cells,” Archives of Virology, Vol.166, No.4, pp. 1203-1211, 2021.
27. [27] F. Superti, M. Agamennone, A. Pietrantoni, and M. G. Ammendolia, “Bovine lactoferrin prevents influenza A virus infection by interfering with the fusogenic function of viral hemagglutinin,” Viruses, Vol.11, No.1, 51, 2019.
28. [28] H. Sano, K. Nagai, H. Tsutsumi, and Y. Kuroki, “Lactoferrin and surfactant protein A exhibit distinct binding specificity to F protein and differently modulate respiratory syncytial virus infection,” European J. of Immunology, Vol.33, No.10, pp. 2894-2902, 2003.
29. [29] F. Berlutti et al., “Antiviral properties of lactoferrin—A natural immunity molecule,” Molecules, Vol.16, No.8, pp. 6992-7018, 2011.
30. [30] M. Yi, S. Kaneko, D. Y. Yu, and S. Murakami, “Hepatitis C virus envelope proteins bind lactoferrin,” J. of Virology, Vol.71, No.8, pp. 5997-6002, 1997.
31. [31] M. Ikeda et al., “Characterization of antiviral activity of lactoferrin against hepatitis C virus infection in human cultured cells,” Virus Research, Vol.66, No.1, pp. 51-63, 2000.
32. [32] Y. Matsuura et al., “Characterization of pseudotype VSV possessing HCV envelope proteins,” Virology, Vol.286, No.2, pp. 263-275, 2001.
33. [33] E. M. El-Fakharany, L. Sánchez, H. A. Al-Mehdar, and E. M. Redwan, “Effectiveness of human, camel, bovine and sheep lactoferrin on the hepatitis C virus cellular infectivity: Comparison study,” Virology J., Vol.10, 199, 2013.
34. [34] A. Cutone et al., “Lactoferrin binding to SARS-CoV-2 spike glycoprotein blocks pseudoviral entry and relieves iron protein dysregulation in several in vitro models,” Pharmaceutics, Vol.14, No.10, 2111, 2022.
35. [35] K. Shin, H. Oda, H. Wakabayashi, K. Yamauchi, and F. Abe, “Effects of lactoferrin on the production of interferon-λ by the human intestinal epithelial cell line HT-29,” Biochemistry and Cell Biology, Vol.95, No.1, pp. 53-56, 2017.
36. [36] T. Kuhara, K. Yamauchi, Y. Tamura, and H. 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. of Interferon & Cytokine Research, Vol.26, No.7, pp. 489-499, 2006.
37. [37] H. Wakabayashi, N. Takakura, K. Yamauchi, and Y. Tamura, “Modulation of immunity-related gene expression in small intestines of mice by oral administration of lactoferrin,” Clinical and Vaccine Immunology, Vol.13, No.2, pp. 239-245, 2006.
38. [38] C. Salaris et al., “Protective effects of lactoferrin against SARS-CoV-2 infection in vitro,” Nutrients, Vol.13, No.2, 328, 2021.
39. [39] M. Kobayashi-Sakamoto et al., “Bovine lactoferrin increases the poly(I:C)-induced antiviral response in vitro,” Biochemistry and Cell Biology, Vol.100, No.4, pp. 338-348, 2022.
40. [40] N. Motoki et al., “Effects of lactoferrin-fortified formula on acute gastrointestinal symptoms in children aged 12–32 months: A randomized, double-blind, placebo-controlled trial,” Frontiers in Pediatrics, Vol.8, 233, 2020.
41. [41] M. Mizuki et al., “Effects of lactoferrin on prevention of acute gastrointestinal symptoms in winter: A randomized, double-blinded, placebo-controlled trial for staff of kindergartens and nursery schools in Japan,” Int. J. of Environmental Research and Public Health, Vol.17, No.24, 9582, 2020.
42. [42] H. Oda et al., “Effects of lactoferrin on infectious diseases in Japanese summer: A randomized, double-blinded, placebo-controlled trial,” J. of Microbiology, Immunology and Infection, Vol.54, No.4, pp. 566-574, 2021.
43. [43] L. Vitetta 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,” Complementary Therapies in Medicine, Vol.21, No.3, pp. 164-171, 2013.
44. [44] T. Tsukahara et al., “The preventive effect of lactoferrin-containing yogurt on gastroenteritis in nursery school children—Intervention study for 15 weeks,” Int. J. of Environmental Research and Public Health, Vol.17, No.7, 2534, 2020.
45. [45] C. Mirabelli et al., “Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19,” Proc. of the National Academy of Sciences, Vol.118, No.36, e2105815118, 2021.
46. [46] R. Reghunathan et al., “Expression profile of immune response genes in patients with severe acute respiratory syndrome,” BMC Immunology, Vol.6, 2, 2005.
47. [47] L. Rosa et al., “Ambulatory COVID-19 patients treated with lactoferrin as a supplementary antiviral agent: A preliminary study,” J. of Clinical Medicine, Vol.10, No.18, 4276, 2021.
48. [48] E. Campione et al., “Lactoferrin as antiviral treatment in COVID-19 management: Preliminary evidence,” Int. J. of Environmental Research and Public Health, Vol.18, No.20, 10985, 2021.
49. [49] F. D. Algahtani et al., “The prospect of lactoferrin use as adjunctive agent in management of SARS-CoV-2 patients: A randomized pilot study,” Medicina, Vol.57, No.8, 842, 2021.