Pattern of lactoferrin anti-influenza virus inhibitory activity

Cover Page

Cite item


Active antigenic drift allows the influenza virus to partially or completely avoid recognition by the immune system. For treatment, inhibitors of the proton-selective ion channel M2 and inhibitors of neuraminidase are used, which have undesirable side effects and provoke the emergence of treatment-resistant strains of the virus. This justifies the need to search for new therapeutic agents. Lactoferrin (LF) is a glycoprotein with a molecular mass of 75—80 kDa, capable for binding metal ions. The highest concentrations of LF are detected in colostrum and milk, a significant amount is deposited in neutrophil granules. The structure of the LF domains of human milk, cow, goat, pig, horse, camel, buffalo is homologous. LF interacts with both specific receptors and endocytosis receptors (LRP), Toll-like, signal receptors on the surface of various cell types. Lactoferrin of humans and animals has a high antiviral activity. This glycoprotein modulates the immune system, including the humoral and cellular immune responses, and regulates redox reactions. However, literature data on the role of this protein in the prevention and treatment of influenza are few. LF inhibitory activity against influenza A and B viruses has been described, including H1N1, H5N1, H7N1, H3N2 strains. It has been established that LF binds virus hemagglutinin, preventing interaction with the cell, blocks programmed cell death through interaction with caspase 3 for preventing the spread of the virus at the later stages of the infection, and blocks virus assembly. Peptides synthesized on the basis of LF C-domain structure demonstrate high inhibitory activity against virus. The use of LF as an adjuvant for vaccines is more effective than of aluminum oxide. Further study of LF effects on influenza virus and on the immune response during infection is necessary to develop new methods of prevention and treatment.

About the authors

V. N. Zorina

Institute of Highly Pure Biopreparations

Author for correspondence.
ORCID iD: 0000-0001-9183-7663

PhD, MD (Biology), Deputy Director for Science.

St. Petersburg

Russian Federation


  1. Зорина В.Н., Зорин Н.А. Белковые компоненты врожденного иммунитета в защите от патогенной инвазии // Журнал микробиологии, эпидемиологии и иммунобиологии. 2013. № 3. С. 111—117.
  2. Actor J.K., Hwang S.A., Kruzel M.L. Lactoferrin as a natural immune modulator. Curr. Pharm. Des., 2009, vol. 15, no. 17, pp. 1956-1973.
  3. Ammendolia M.G., Agamennone M., Pietrantoni A., Lannutti F., Siciliano R.A., De Giulio B., Amici C., Superti F. Bovine lactoferrin-derived peptides as novel broad-spectrum inhibitors of influenza virus. Pathog. Glob. Health., 2012, vol. 106, no. 1, pp. 12-19. doi: 10.1179/2047773212Y.0000000004
  4. Berlutti F., Pantanella F., Natalizi T., Frioni A., Paesano R., Polimeni A., Valenti P. Antiviral properties of lactoferrin — a natural immunity molecule. Molecules, 2011, vol. 16, no. 8, pp. 6992-7018. doi: 10.3390/molecules16086992
  5. Carvalho C.A.M., Casseb S.M.M., Gonsalves R.B., Silva E.V.P., Gomes A.M.O., Vasconcelos P.F.C. Bovine lactoferrin activity against Chikungunya and Zika viruses. J. Gen. Virol., 2017, vol. 98, no. 7, pp. 1749-1754. doi: 10.1099/jgv.0.000849
  6. Chen J.M., Fan Y.C., Lin J.W., Chen Y.Y., Hsu W.L., Chiou S.S. Bovine lactoferrin inhibits dengue virus infectivity by interacting with heparan sulfate, low-density lipoprotein receptor, and DC-SIGN. Int. J. Mol. Sci., 2017, vol. 18, no. 9: E1957. doi: 10.3390/ijms18091957
  7. Kawasaki Y., Isoda H., Shinmoto H., Tanimoto M., Dosako S., Idota T., Nakajima I. Inhibition by kappa-casein glycomacropep-tide and lactoferrin of influenza virus hemagglutination. Biosci BiotechnolBiochem., 1993, vol. 57, no. 7, pp. 1214-1215.
  8. Legrand D., Elass E., Carpentier M., Mazurier J. Lactoferrin: a modulator of immune and inflammatory responses. Cell. Mol. Life Sci., 2005, vol. 62, no. 22,pp. 2549-2559. doi: 10.1007/s00018-005-5370-2
  9. Levay P.F., Viljoen M. Lactoferrin: a general review. Haematologica, 1995, vol. 80, pp. 252-267.
  10. Moguilevsky N., Retegui L.A., Masson P.L. Comparison of human lactoferrins from milk and neutrophilic leucocytes. Relative molecular mass, isoelectric point, iron-binding properties and uptake by the liver. Biochem. J, 1985, vol. 229, pp. 353-359. doi: 10.1042/bj2290353
  11. Ng T.B., Cheung R.C., Wong J.H., Wang Y., Ip D.T., Wan D.C., Xia J. Antiviral activities of whey proteins. Appl. Microbiol. Biotechnol,, 2015, vol. 99, no. 17,pp. 6997-7008. doi: 10.1007/s00253-015-6818-4
  12. Pandey R.P., Kim D.H., Woo J., Song J., Jang S.H., Kim J.B., Cheong K.M., Oh J.S., Sohng J.K. Broad-spectrum neutralization of avian influenza viruses by sialylated human milk oligosaccharides: in vivo assessment of 3’-sialyllactose against H9N2 in chickens. Sci. Rep., 2018, vol. 8, no. 1:2563. doi: 10.1038/s41598-018-20955-4
  13. Pietrantoni A., Dofrelli E., Tinari A., Ammendolia M.G., Puzelli S., Fabiani C., Donatelli I., Superti F. Bovine lactoferrin inhibits influenza A virus induced programmed cell death in vitro. Biometals, 2010, vol. 23, no. 3, pp. 465—475. doi: 10.1007/s10534-010-9323-3
  14. Pietrantoni A., Ammendolia M.G., Superti F. Bovine lactoferrin: involvement of metal saturation and carbohydrates in the inhibition of influenza virus infection. Biochem. Cell Biol, 2012, vol. 90, no. 3, pp. 442—448. doi: 10.1139/o11-072
  15. Puddu P., Latorre D., Carollo M., Catizone A., Ricci G., Valenti P., Gessani S. Bovine lactoferrin counteracts Toll-like receptor mediated activation signals in antigen presenting cells. PLoS One, 2011, vol. 6, no. 7: e22504. doi: 10.1371/journal.pone.0022504
  16. Scala M.C., Sala M., Pietrantoni A., Spensiero A., Di Micco S., Agamennone M., Bertamino A., Novellino E., Bifulco G., Gomez-Monterrey I.M., Superti F., Campiglia P. Lactoferrin-derived peptides active towards influenza: identification of three potent tetrapeptide inhibitors. Sci. Rep., 2017, vol. 7, no. 1, pp. 10593. doi: 10.1038/s41598-017-10492-x
  17. Sharma S., Sinha M., Kaushik S., Kaur P., Singh T.P. C-lobe of lactoferrin: the whole story of the half-molecule. Biochem. Res. Int, 2013, vol. 2013, 8p. doi: 10.1155/2013/271641
  18. Sherman M.P., Pritzl C.J., Xia C., Miller M.M., Zaghouani H., Hahm B. Lactoferrin acts as an adjuvant during influenza vaccination of neonatal mice. Biochem. Biophys. Res. Commun., 2015, vol. 467, no. 4, pp. 766—770. doi: 10.1016/j.bbrc.2015.10.067
  19. Shin K., Wakabayashi H., Yamauchi K., Teraguchi S., Tamura Y., Kurokawa M., Shiraki K. Effects of orally administered bovine lactoferrin and lactoperoxidase on influenza virus infection in mice. J. Med. Microbiol., 2005, vol. 54, pt. 8, pp. 717—723. doi: 10.1099/jmm.0.46018-0
  20. Siqueiros-Cendon T., Arevalo-Gallegos S., Iglesias-Figueroa B.F., Garcla-Montoya I.A., Salazar-Martlnez J., Rascon-Cruz Q. Immunomodulatory effects of lactoferrin. Acta Pharmacol. Sin., 2014, vol. 35, no. 5, pp. 557—566. doi: 10.1038/aps.2013.200
  21. Spadaro M., Montone M., Arigoni M., Cantarella D., Forni G., Pericle F., Pascolo S., Calogero R.A., Cavallo F. Recombinant human lactoferrin induces human and mouse dendritic cell maturation via Toll-like receptors 2 and 4. FASEB J., 2014, vol. 28, no. 1, pp. 416-429. doi: 10.1096/fj.13-229591
  22. Taha S.H., Mehrez M.A., Sitohy M.Z., Abou Dawood A.G., Abd-El Hamid M.M., Kilany W.H. Effectiveness of esterified whey proteins fractions against Egyptian Lethal Avian Influenza A (H5N1). Virol J., 2010, vol. 7:330. doi: 10.1186/1743-422X-7-330
  23. Van Splunter M., Perdijk O., Fick-Brinkhof H., Feitsma A.L., Floris-Vollenbroek E.G., Meijer B., Brugman S., Savelkoul H.F.J., van Hoffen E., van Neerven R.J.J. Bovine lactoferrin enhances TLR7-mediated responses in plasmacytoid dendritic cells in elderly women: results from a nutritional intervention study with bovine lactoferrin, GOS and vitamin D. Front. Immunol., 2018, vol. 9: 2677. doi: 10.3389/fimmu.2018.02677
  24. Wakabayashi H., Oda H., Yamauchi K., Abe F. Lactoferrin for prevention of common viral infections. J. Infect. Chemother., 2014, vol. 20,pp. 666- 671. doi: 10.1016/j.jiac.2014.08.003
  25. Wang M., Sun Z., Yu T., Ding F., Li L., Wang X., Fu M., Wang H., Huang J., Li N., Dai Y. Large-scale production of recombinant human lactoferrin from high-expression, marker-free transgenic cloned cows. Sci. Rep., 2017, vol. 7, no. 1: 10733. doi: 10.1038/s41598-017-11462-z
  26. Yamauchi K., Wakabayashi H., Shin K., Takase M. Bovine lactoferrin: benefits and mechanism of action against infections. Biochem. Cell Biol., 2006, vol. 84, no. 3, pp. 291-296. doi: 10.1139/o06-054
  27. Yang D., de la Rosa G., Tewary P., Oppenheim J.J. Alarmins link neutrophils and dendritic cells. Trends Immunol., 2009, vol. 30, no. 11,pp. 531-537. doi: 10.1016/
  28. Yemets A.I., Tanasienko I.V., Krasylenko Y.A., Blume Y.B. Plant-based biopharming of recombinant human lactoferrin. Cell Biol. Int., 2014, vol. 38, pp. 989-1002. doi: 10.1002/cbin.10304

Supplementary files

There are no supplementary files to display.

Copyright (c) 2020 Zorina V.N.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies