Please note our website will be undergoing maintenance on Tuesday, May 28, 2024. e-Commerce transactions and new registrations will be temporarily unavailable during this time. We apologize for any inconvenience this may cause.
Free access

Lactoferrin extends its reach into South America

Publication: Biochemistry and Cell Biology
22 February 2021

Introduction

The 14th International Conference on Lactoferrin, Structure, Function, and Applications was held on 4–8 November 2019, in a new hotel conference center in the beautiful Miraflores district of Lima, Peru. Previous Lactoferrin meetings have been held every 2 years in various locations around the world, alternating between the America’s, Asia, and Europe, but this was the very first time that the meeting was actually held in South America. The Lactoferrin meetings normally attract a wide international audience, and this meeting was no exception, with registered participants coming from all continents. Furthermore, the organizers were happy to see that many scientists from different South American countries attended and actively participated in the biennial meeting. From the enthusiasm and the high quality of the presentations of all participants, it is clear that lactoferrin research has now extended its reach across the entire globe.
Lactoferrin (LF) is an abundantly present iron-binding glycoprotein that was first described as a major component of milk some 80 years ago. It has been known for some time that LF levels in milk are particularly high in colostrum, suggesting that it can play an important role in infant nutrition or by providing protection against infections for neonates and infants. The protein is also present in high amounts in all neutrophil granules and in many other bodily exocrine secretions, where it is thought to have immunomodulatory and host-defence functions (Vogel 2012; Rosa et al. 2017). The three-dimensional crystal structure of the iron-binding protein has been known for some time (Baker and Baker 2012), but many aspects of its physiological actions still remain unclear, and these warrant continued research efforts. Because bovine LF shares many of the beneficial properties of the human LF protein, and the former can be purified on a large commercial scale from cow’s milk, much of the ongoing physiological, preclinical, and clinical research is focused on the effects of the bovine LF protein. Indeed, the wide availability of bovine LF has spawned an interest in the use of this protein as a health promoting immunostimulant, or as an alternative to antibiotics, or as an anticancer agent.
A special highlight of the meeting was a dedicated symposium on the role of LF in neonatal sepsis. Results from a variety of published clinical trials that have been carried out over the years in different locations around the world were discussed. Some early randomized clinical trials had given very positive outcomes (Manzoni et al. 2009), leading to recommendations for oral bovine LF supplementation to prevent the onset of sepsis in neonates. However, more recent larger scale trials have not been able to confirm such effects (Griffiths et al. 2019). During this symposium, a number of new trials and some re-analyses of earlier results were discussed for the ELFIN, LIFT, and NEOLACTO trials. Several contributions are provided in this special issue that describe and extend on the original neonatal sepsis studies (Berrington et al. 2020; Kaufman et al. 2020; Ochoa et al. 2020; Pammi et al. 2020). Moreover, the first direct evidence for the transfer of enteral bovine LF to the bloodstream in preterm infants was also presented during the meeting (Itell et al. 2020), providing an important causal link between oral administration of LF and its systemic effects. While it is still not clear why there is such variability in the outcome of the neonatal sepsis trials, it was extensively discussed that LF samples obtained from different manufacturers can display widely distinct biological activities (Lönnerdal et al. 2020), probably reflecting the different purification, production, and storage procedures from the various bovine LF manufacturers. Such factors would therefore need to be carefully controlled in future clinical trials, to make the trial results more reproducible.
Many other physiological and preclinical effects of LF were also addressed, for example, transcriptome profiling was used to demonstrate the widespread systemic effects of oral recombinant human LF administration (Kruzel et al. 2020). The effects of LF on various bacterial infections and on several relevant innate immune receptors were studied in cell cultures and in animal models by a number of groups (Buey et al. 2020; Dierick et al. 2020; Hao et al. 2020; Nguyen et al. 2020), while others demonstrated the beneficial effects of LF administration during oral pathologies in humans (Rosa et al. 2020). In other studies it was also shown that LF levels in cervical fluid may impact the outcome of in vitro fertilizations (Massa et al. 2020); an intriguing observation that could have widespread implications. Other investigators suggested that the iron-binding properties of LF may have a protective effect during hematoma detoxification (Zhao et al. 2020). At the biochemical level, interactions between LF and bacterial receptors were analyzed (Ostan et al. 2021), as well as the interactions of LF with myeloperoxidase and low-density lipoproteins (Vasilyev et al. 2020). Moreover, the glycosylation patterns of LF were carefully analyzed, as these may affect the biological activities of the protein (Zlatina and Galuska 2020).
It has been known for some time that various peptides can be generated through proteolysis from bovine and human LF, and that these peptides can have important host-defense activities. Chemical synthesis of peptides is nowadays a routine procedure, and numerous research groups around the world have studied the effects of various lactoferrin-derived or lactoferrin-inspired synthetic peptides. Indeed, some LF-inspired anticancer peptides are currently already being tested in phase 2 clinical trials (Sveinbjornsson et al. 2017). During the Lactoferrin meeting, Ligtenberg et al. (2021), provided a comprehensive overview of antimicrobial results against various pathogenic bacteria that have been obtained with the so-called LF-chimera, a peptide adduct of the lactoferricin and lactoferrampin regions of bovine LF. At the same time Ramamourthy and Vogel (2020) reported on the antibiofilm activities of relatively short combined LF-peptides against Pseudomonas aeruginosa, a major human pathogen. Since it is now thought that 80% of human bacterial infections arise from bacterial biofilms, rather than from planktonic bacteria, such contributions open up new directions for research on LF-peptides. The group of Leon-Sicairos also reported on cell culture studies of the cytotoxic and potential anticancer activities of bovine LF and several LF-derived peptides (Ramirez-Sanchez et al. 2020). Along similar lines, Tanaka et al. (2020) studied the beneficial effects of intact LF in a mouse model of colon cancer.
Finally, there were a few presentations at the meeting that focused on the antiviral effects of LF. These properties are known to affect many different viruses and they have been extensively studied in the past (for review see Berlutti et al. 2011). At the meeting, Oda et al. (2020) discussed new studies in cell cultures and at the population level illustrating the beneficial protective effects of LF during human norovirus infections. The Lima meeting was held in November 2019, at which point the COVID-19 pandemic was still a total unknown. At the time of writing this introduction, the pandemic, which is caused by infections of the SARS-CoV-2 coronavirus, has affected millions of people around the globe and caused significant mortality. Consequently, a renewed interest in LF as a protective agent against coronavirus infections has emerged, and several trials were initiated in 2020 in an attempt to demonstrate such beneficial effects. Be that as it may, levels of LF were earlier shown to increase dramatically in patients that had been infected with the closely-related SARS-CoV-1 coronavirus during the original SARS pandemic in 2003 (Reghunathan et al. 2005). Also, in vitro studies with SARS-CoV-1, which shares 80% sequence identity with SARS-CoV-2, have already suggested that LF can have a protective effect and block cell entry of such coronaviruses (Lang et al. 2011). Both these coronaviruses target the same ACE2 receptor on cells through their spike proteins (Shang et al. 2020). Thus, it is not surprising that various current studies are focusing on trying to delineate the role of LF, both as a biomarker of disease, and as a potential treatment against SARS-CoV-2 (Campione et al. 2020; Mirabelli et al. 2020). While it is too early yet to report on the outcome of these studies, such work clearly sets the stage for exciting discussions during the upcoming 15th Lactoferrin meeting, which will be held as a virtual or hybrid meeting in Beijing, China, in the Fall of 2021.

References

Baker H.M. and Baker E.N. 2012. A structural perspective on lactoferrin function. Biochem Cell Biol. 90: 320–328.
Berlutti F., Pantanella F., Natalizi T., Frioni A., Paesano R., Polimeni A., and Valenti P. 2011. Antiviral properties of lactoferrin—a natural immunity molecule. Molecules, 16: 6992–7018.
Berrington J.E., McGuire W., and Embleton N.D. 2020. ELFIN, the United Kingdom preterm lactoferrin trial: interpretation and future questions. Biochem. Cell Biol. 99: 1–6.
Buey B., Bellés A., Latorre E., Abad I., Péres M.D., Grasa L., et al. 2020. Comparative effect of bovine buttermilk, whey, and lactoferrin on the innate immunity receptors and oxidative status of intestinal epithelial cells. Biochem. Cell Biol. 99: 54–60.
Campione E., Cosio T., Rosa L., Lanna C., Di Girolamo S., and Gaziano R. 2020. Lactoferrin as protective natural barrier of respiratory and intestinal mucosa against coronavirus infection and inflammation. Int. J. Mol. Sci. 21: 4903.
Dierick M., Vanrompay D., Devriendt B., and Cox E. 2020. Lactoferrin, a versatile natural antimicrobial glycoprotein that modulates the host’s innate immunity. Biochem. Cell Biol. 99: 61–65.
Griffiths J., Jenkins P., Vargova M., Bowler U., Juszcak E., King A., et al. 2019. Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial. Lancet, 393: 423–433.
Hao D., Wang J., Teng D., Mao R., Yang N., and Ma X. 2020. A prospective on multiple biological activities of lactoferrin contributing to piglet welfare. Biochem. Cell Biol. 99: 66–72.
Itell H.L., Berenz A., Mangan R.J., Permar S.R., and Kaufman D.A. 2020. Systemic and mucosal levels of lactoferrin in very low birth weight infants supplemented with bovine lactoferrin. Biochem. Cell Biol. 99: 25–34.
Kaufman D.A., Berenz A., Itell H.L., Conaway M., Blackman A., Nataro J.P., and Permar S.R. 2020. Dose escalation study of bovine lactoferrin in preterm infants: getting the dose right. Biochem. Cell Biol. 99: 7–13.
Kruzel M.L., Olszewska P., Pazdrak B., Krupinska A.M., and Actor J.K. 2020. New insights into the systemic effects of oral lactoferrin: transcriptome profiling. Biochem. Cell Biol. 99: 46–53.
Lang J., Yang N., Deng J., Liu K., Yang P., Zhang G., and Jiang C. 2011. Inhibition of SARS pseudovirus cell entry by lactoferrin binding to heparan sulfate proteoglycans. PLoS One, 6: e23710.
Ligtenberg A.J., Bikker F.J., and Bolscher J.G.M. 2021. LFchimera: a synthetic mimic of the two antimicrobial domains of bovine lactoferrin. Biochem. Cell Biol. 99: 129–138.
Lönnerdal B., Du X., and Jiang R. 2020. Biological activities of commercial bovine lactoferrin sources. Biochem. Cell Biol. 99: 35–45.
Manzoni P., Rinaldi M., Cattani S., et al. 2009. Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates: A Randomized Trial. JAMA, 302(13): 1421–1428.
Massa E., Pelusa F., Lo Celso A., Madariaga M.J., Filocco L., Morents C., and Ghersevich S. 2020. Lactoferrin levels in cervical fluid from in vitro fertilization (IVF) patients — correlation with IVF parameters. Biochem. Cell Biol. 99: 91–96.
Mirabelli C., Wotring J.W., Zhang C.J., McCarty S.M., Fursmidt R., Kadambi N.S., et al. 2020. Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19. BioRxiv, [In press].
Nguyen T.K.T., Niaz Z., d’Aigle J., Hwang S.-A., Kruzel M.L., and Actor J. 2020. Lactoferrin reduces mycobacterial M1-type inflammation induced with trehalose 6,6′-dimycolate and facilitates the entry of fluoroquinolone into granulomas. Biochem. Cell Biol. 99: 73–80.
Ochoa T.J., Loli S., Mendoza K., Carcamo C., Bellomo S., Cam L., et al. 2020. Effect of bovine lactoferrin on prevention of late-onset sepsis in infants <1500g: a pooled analysis of individual patient data from two randomized controlled trials. Biochem. Cell Biol. 99: 14–19.
Oda H., Kolawole A., Mirabelli C., Wakabayashi H., Tanaka M., Yamauchi K., et al. 2020. Antiviral effects of bovine lactoferrin on human norovirus. Biochem. Cell Biol. 99: 167–173.
Ostan N.K.H., Moraes T.F., and Schryvers A.B. 2021. Lactoferrin receptors in Gram-negative bacteria: an evolutionary perspective. Biochem. Cell Biol. 99: 102–109.
Pammi M., Preidis G.A., and Tarnow-Mordi W.O. 2020. Evidence from systematic reviews of randomized trials on enteral lactoferrin supplementation in preterm neonates. Biochem. Cell Biol. 99: 20–24.
Ramamourthy G. and Vogel H.J. 2020. Antibiofilm activity of lactoferrin-derived synthetic peptides against Pseudomonas aeruginosa PAO1. Biochem. Cell Biol. 99: 139–149.
Ramirez-Sanchez D.A., Arredondo-Beltran I.G., Canizalez-Roman A., Flores-Villaseñor H., Nazmi K., Bolscher J.G.M., and Leon-Sicairos N. 2020. Bovine lactoferrin and lactoferrin peptides affect endometrial and cervical cancer cell lines. Biochem. Cell Biol. 99: 150–159.
Reghunathan R., Jayapal M., Hsu L.Y., Chng H.H., Tai D., Leung B.P., and Melendez A.J. 2005. Expression profile of immune response genes in patients with Severe Acute Respiratory Syndrome. BMC Immunol.
Rosa L., Cutone A., Lepanto M.S., Paesano R., and Valenti P. 2017. Lactoferrin: a natural glycoprotein involved in iron and inflammatory homeostasis. Int. J. Mol. Sci. 18: 1985.
Rosa L., Lepanto M.S., Cutone A., Ianiro G., Pernarella S., Sangermano R., et al. 2020. Lactoferrin and oral pathologies: a therapeutic treatment. Biochem. Cell Biol. 99: 81–90.
Shang J., Ye G., Shi K., Wan Y., Luo C., Aihara H., et al. 2020. Structural basis of receptor recognition by SARS-CoV-2. Nature, 581: 221–224.
Sveinbjornsson B., Camilio K., Haug B.E., and Rekdal O. 2017. LTX-315: a first in class oncolytic peptide that reprograms the tumor microenvironment. Future Med. Chem. 9(12): 1339–1344.
Tanaka H., Gunasekaran S., Saleh D.M., Alexander W.T., Alexander D.B., Ohara H., and Tsuda H. 2020. Effects of oral bovine lactoferrin on a mouse model of inflammation associated colon cancer. Biochem. Cell Biol. 99: 160–166.
Vasilyev V.B., Sokolov A.V., Kostevich V.A., Elizarova A.Yu., Gorbunov N.P., and Panasenko O.M. 2020. Binding of lactoferrin to the surface of low-density lipoproteins modified by myeloperoxidase prevents intracellular cholesterol accumulation by human blood monocytes. Biochem. Cell Biol. 99: 110–117.
Vogel H.J. 2012. Lactoferrin, a bird’s eye view. Biochem Cell Biol. 90: 233–244.
Zhao X., Kruzel M.A.J., and Aronowski J. 2020. Lactoferrin and hematoma detoxification after intracerebral hemorrhage. Biochem. Cell Biol. 99: 97–101.
Zlatina K. and Galuska S. 2020. The N-glycans of lactoferrin: more than just a sweet decoration. Biochem. Cell Biol. 99: 118–128.

Information & Authors

Information

Published In

cover image Biochemistry and Cell Biology
Biochemistry and Cell Biology
Volume 99Number 1February 2021
Pages: v - vii

History

Version of record online: 22 February 2021

Notes

This Introduction is one of a selection of papers from the 14th International Conference on Lactoferrin Structure, Function, and Applications, held in Lima, Peru, 4–8 November 2019.

Permissions

Request permissions for this article.

Authors

Affiliations

Theresa J. Ochoa [email protected]
Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru.
Hans J. Vogel [email protected]
Biochemistry Research Group, Department of Biological Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada.

Notes

Copyright remains with the author(s) or their institution(s). Permission for reuse (free in most cases) can be obtained from copyright.com.

Metrics & Citations

Metrics

Other Metrics

Citations

Cite As

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.

Cited by

1. Tryptophan- and arginine-rich antimicrobial peptides: Anti-infectives with great potential
2. Lactoferrin, a Great Wall of host-defence?

View Options

View options

PDF

View PDF

Get Access

Login options

Check if you access through your login credentials or your institution to get full access on this article.

Subscribe

Click on the button below to subscribe to Biochemistry and Cell Biology

Purchase options

Purchase this article to get full access to it.

Restore your content access

Enter your email address to restore your content access:

Note: This functionality works only for purchases done as a guest. If you already have an account, log in to access the content to which you are entitled.

Media

Media

Other

Tables

Share Options

Share

Share the article link

Share on social media

Cookies Notification

We use cookies to improve your website experience. To learn about our use of cookies and how you can manage your cookie settings, please see our Cookie Policy.
×