Effects of different sources of lactoferrin on cytokine response to SARS-COV-2, respiratory syncytial virus, and rotavirus infection in vitro
Abstract
Lactoferrin (Lf) is a multifunctional iron-binding glycoprotein, involved in a wide range of bioactivities, including immunomodulatory and antiviral activities. Lf in human milk and bovine Lf added to infant formula may provide some protection against viral infections. However, functions of Lfs from different sources may differ due to varying manufacturing processes and posttranslational modifications. Here, effects of Lfs (11 commercial bovine milk Lfs, 2 recombinant Lfs, and native human/bovine milk Lf) on cytokine responses to virus infection were examined by infecting human intestinal epithelial cells (Caco-2 cells) with rotavirus (naked) or normal human bronchial epithelial cells (BEAS-2B cells) with respiratory syncytial virus (RSV, enveloped) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein 1. Effects of Lf on viral infection were evaluated by quantitative real-time polymerase chain reaction analysis of transcripts of cytokines/chemokines (TNF-α, IL-1β, IL-6, IL-8, IL-10, IFN-β, and CXCL10). Our results show that viral infection changes transcription of these cytokines and that Lfs significantly and variously influence immune responses to rotavirus, RSV, and SARS-CoV-2 in vitro. Thus, Lf may provide protection against virus infection by down-regulating pro–inflammatory cytokine/chemokine responses. Recombinant bovine and human Lf show similar effects as bovine milk Lfs suggesting that different posttranslational modifications do not affect the antiviral activity on cytokine response.
Get full access to this article
View all available purchase options and get full access to this article.
References
Almond R.J., Flanagan B.F., Antonopoulos A., Haslam S.M., Dell A., Kimber I., Dearman R.J. 2013. Differential immunogenicity and allergenicity of native and recombinant human lactoferrins: role of glycosylation. Eur. J. Immunol. 43(1): 170–181.
Amimo J.O., Raev S.A., Chepngeno J., Mainga A.O., Guo Y., Saif L., Vlasova A.N. 2021. Rotavirus interactions with host intestinal epithelial cells. Front. Immunol. 12: 793841.
Barboza M., Pinzon J., Wickramasinghe S., Froehlich J.W., Moeller I., Smilowitz J.T., et al. 2012. Glycosylation of human milk lactoferrin exhibits dynamic changes during early lactation enhancing its role in pathogenic bacteria-host interactions. Mol. Cell. Proteomics, 11(6): M111.015248.
Bethell D.R., Huang J. 2004. Recombinant human lactoferrin treatment for global health issues: iron deficiency and acute diarrhea. Biometals, 17(3): 337–342.
Cheng J.B., Wang J.Q., Bu D.P., Liu G.L., Zhang C.G., Wei H.Y., et al. 2008. Factors affecting the lactoferrin concentration in bovine milk. J. Dairy Sci. 91(3): 970–976.
Cutone A., Rosa L., di Patti M.C.B., Iacovelli F., Conte M.P., Ianiro G., et al. 2022. Lactoferrin binding to SARS-CoV-2 spike glycoprotein blocks pseudoviral entry and relieves iron protein dysregulation in several in vitro models. Pharmaceutics, 14(10): 2111.
Egashira M., Takayanagi T., Moriuchi M., Moriuchi H. 2007. Does daily intake of bovine lactoferrin-containing products ameliorate rotaviral gastroenteritis? Acta Paediatr. 96(8): 1242–1244.
Fischer R., Debbabi H., Dubarry M., Boyaka P., Tomé D. 2006. Regulation of physiological and pathological Th1 and Th2 responses by lactoferrin. Biochem. Cell Biol. 84(3): 303–311.
He S.-T., Qin H., Guan L., Liu K., Hong B., Zhang X., et al. 2023. Bovine lactoferrin inhibits SARS-CoV-2 and SARS-CoV-1 by targeting the RdRp complex and alleviates viral infection in the hamster model. J. Med. Virol. 95(1): e28281.
Hu B., Huang S., Yin L. 2021. The cytokine storm and COVID-19. J. Med. Virol. 93(1): 250–256.
Ioi H., Kawashima H., Nishimata S., Watanabe Y., Yamanaka G., Kashiwagi Y., et al. 2006. A case of Reye syndrome with rotavirus infection accompanied with high cytokines. J. Infect. 52(4): e124–e128.
Ismail S., Unger S., Budylowski P., Poutanen S., Yau Y., Jenkins C., et al. 2024. SARS-CoV-2 antibodies and their neutralizing capacity against live virus in human milk after COVID-19 infection and vaccination: prospective cohort studies. Am. J. Clin. Nutr. 119(2): 485–495.
Karav S., German J.B., Rouquié C., Le Parc A., Barile D. 2017. Studying lactoferrin N-glycosylation. Int. J. Mol. Sci. 18(4): 870.
Kell D.B., Heyden E.L., Pretorius E. 2020. The biology of lactoferrin, an iron-binding protein that can help defend against viruses and bacteria. Front. Immunol. 11: 1221.
Krolitzki E., Schwaminger S.P., Pagel M., Ostertag F., Hinrichs J., Berensmeier S. 2022. Current practices with commercial scale bovine lactoferrin production and alternative approaches. Int. Dairy J. 126: 105263.
Legrand D. 2016. Overview of lactoferrin as a natural immune modulator. J. Pediatr. 173: S10–S15.
Li W., Liu B., Lin Y., Xue P., Lu Y., Song S., et al. 2022. The application of lactoferrin in infant formula: the past, present and future. Crit. Rev. Food Sci. Nutr. 64, 1–20.
Lien E., Jackson J., Kuhlman C., Pramuk K., Lönnerdal B., Janszen D. 2004. Variations in concentrations of lactoferrin in human milk: a nine country survey. Adv. Exp. Med. Biol. 554: 423–426.
Lönnerdal B., Du X., Jiang R. 2021. Biological activities of commercial bovine lactoferrin sources. Biochem. Cell. Biol. 99(1): 35–46.
Lönnerdal B., Jiang R., Du X. 2011. Bovine lactoferrin can be taken up by the human intestinal lactoferrin receptor and exert bioactivities. J. Pediatr. Gastroenterol. Nutr. 53(6): 606–614.
Mirabelli C., Wotring J.W., Zhang C.J., McCarty S.M., Fursmidt R., Pretto C.D., et al. 2021. Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19. Proc. Natl. Acad. Sci. 118(36): e2105815118.
Parrón J.A., Ripollés D., Ramos S.J., Pérez M.D., Semen Z., Rubio P., et al. 2018. Antirotaviral potential of lactoferrin from different origin: effect of thermal and high pressure treatments. Biometals, 31(3): 343–355.
Puddu P., Valenti P., Gessani S. 2009. Immunomodulatory effects of lactoferrin on antigen presenting cells. Biochimie, 91(1): 11–18.
Redwan E.M., Uversky V.N., El-Fakharany E.M., Al-Mehdar H. 2014. Potential lactoferrin activity against pathogenic viruses. C.R. Biol. 337(10): 581–595.
Rosa L., Cutone A., Conte M.P., Campione E., Bianchi L., Valenti P. 2023. An overview on in vitro and in vivo antiviral activity of lactoferrin: its efficacy against SARS-CoV-2 infection. Biometals, 36(3): 417–436.
Sano H., Nagai K., Tsutsumi H., Kuroki Y. 2003. Lactoferrin and surfactant protein A exhibit distinct binding specificity to F protein and differently modulate respiratory syncytial virus infection. Eur. J. Immunol. 33(10): 2894–2902.
Superti F., Ammendolia M.G., Valenti P., Seganti L. 1997. Antirotaviral activity of milk proteins: lactoferrin prevents rotavirus infection in the enterocyte-like cell line HT-29. Med. Microbiol. Immunol. 186(2–3): 83–91.
Superti F., Siciliano R., Rega B., Giansanti F., Valenti P., Antonini G. 2001. Involvement of bovine lactoferrin metal saturation, sialic acid and protein fragments in the inhibition of rotavirus infection. Biochim. Biophys. Gen. Sub. 1528(2–3): 107–115.
Tonon K.M., Chutipongtanate S., Morrow A.L., Newburg D.S. 2024. Human milk oligosaccharides and respiratory syncytial virus infection in infants. Adv. Nutr. 15, 100218.
Vishwanath-Deutsch R., Dallas D.C., Besada-Lombana P., Katz L., Conze D., Kruger C., et al. 2024. A review of the safety evidence on recombinant human lactoferrin for use as a food ingredient. Food Chem. Toxicol. 189: 114727.
Wakabayashi H., Oda H., Yamauchi K., Abe F. 2014. Lactoferrin for prevention of common viral infections. J. Infect. Chemother. 20(11): 666–671.
Walsh K.B., Teijaro J.R., Brock L.G., Fremgen D.M., Collins P.L., Rosen H., Oldstone M.B.A. 2014. Animal model of respiratory syncytial virus: CD8+ T cells cause a cytokine storm that is chemically tractable by sphingosine-1-phosphate 1 receptor agonist therapy. J. Virol. 88(11): 6281–6293.
Wang B., Timilsena Y.P., Blanch E., Adhikari B. 2019. Lactoferrin: structure, function, denaturation and digestion. Crit. Rev. Food Sci. Nutr. 59(4): 580–596.
Wu H., Wang Y., Li H., Meng L., Zheng N., Wang J. 2021. Effect of food endotoxin on infant health. Toxins, 13(5): 298.
Zhao B.S., Roundtree I.A., He C. 2017. Post-transcriptional gene regulation by mRNA modifications. Nat. Rev. Mol. Cell Biol. 18(1): 31–42.
Zhou Y., Qiao H., Yin N., Chen L., Xie Y., Wu J., et al. 2019. Immune and cytokine/chemokine responses of PBMCs in rotavirus-infected rhesus infants and their significance in viral pathogenesis. J. Med. Virol. 91(8): 1448–1469.
Zhu N., Zhang D., Wang W., Li X., Yang B., Song J., et al. 2020. A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med. 382(8): 727–733.
Zlatina K., Galuska S.P. 2021. The N-glycans of lactoferrin: more than just a sweet decoration. Biochem. Cell Biol. 99(1): 117–127.
Information & Authors
Information
Published In
Biochemistry and Cell Biology
Volume 103 • 2025
Pages: 1 - 12
History
Received: 28 June 2024
Accepted: 7 March 2025
Accepted manuscript online: 14 March 2025
Version of record online: 17 April 2025
Notes
This paper is part of a Collection based on presentations at the “2023 XVI International Lactoferrin conference,” held on November 6 to 10, 2023 in Rome, Italy. https://cdnsciencepub.com/topic/bcb-lactoferrinconference2023.
Copyright
© 2025 The Authors. Permission for reuse (free in most cases) can be obtained from copyright.com.
Data Availability Statement
Data generated or analyzed during this study are available from the corresponding author upon reasonable request.
Key Words
Authors
Author Contributions
Conceptualization: RJ, BL
Data curation: RJ, XD
Formal analysis: RJ
Funding acquisition: BL
Methodology: RJ, XD
Supervision: BL
Writing – original draft: RJ
Writing – review & editing: RJ, BL
Competing Interests
The authors declare there are no competing interests.
Funding Information
TurtleTree Labs, Woodland, California, USA
Mead Johnson Nutrition and Health Innovation Institute, Hongkong
Metrics & Citations
Metrics
Other Metrics
Citations
Cite As
Rulan Jiang, Xiaogu Du, and Bo Lönnerdal. 2025. Effects of different sources of lactoferrin on cytokine response to SARS-COV-2, respiratory syncytial virus, and rotavirus infection in vitro. Biochemistry and Cell Biology.
103: 1-12.
https://doi.org/10.1139/bcb-2024-0146
Export Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.
There are no citations for this item
View Options
Login options
Check if you access through your login credentials or your institution to get full access on this article.