Immunomodulatory effect of bovine lactoferrin during SARS-CoV-2 infection

Silva et al., Frontiers in Immunology, doi:10.3389/fimmu.2024.1456634

Oct 2024

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In Silico, In Vitro, and mouse study showing immunomodulatory effects of bovine lactoferrin (bLf) during SARS-CoV-2 infection. In Silico analysis showed bLf strongly binds to TLR4 and NF-kB. In Vitro, bLf modulated frequencies of NK and T cell subsets and cytokine levels in PBMCs from COVID-19 patients. In SARS-CoV-2 infected K18-hACE2 mice, bLf treatment increased pro-inflammatory cytokines systemically and in the lungs, and homeostatic iron metabolism in the brain. Results suggest bLf's immunomodulatory effects depend on infection stage, with pro-inflammatory effects in acute infection and normalization of circulating immune cells in convalescence. Authors propose bLf as a potential supportive immunomodulatory therapy for COVID-19 to promote immune homeostasis.

17 preclinical studies support the efficacy of lactoferrin for COVID-19:

3 In Silico studies1-3

12 In Vitro studies1,2,4-13

2 In Vivo animal studies1,14

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1. Silva et al., Immunomodulatory effect of bovine lactoferrin during SARS-CoV-2 infection, Frontiers in Immunology, doi:10.3389/fimmu.2024.1456634.frontiersin.org, doi.org.

2. Cutone et al., Lactoferrin binding to Sars-CoV-2 Spike glycoprotein protects host from infection, inflammation and iron dysregulation., Research Square, doi:10.21203/rs.3.rs-1605740/v1.researchsquare.com, doi.org.

3. Miotto et al., Molecular Mechanisms Behind Anti SARS-CoV-2 Action of Lactoferrin, Frontiers in Molecular Biosciences, doi:10.3389/fmolb.2021.607443.frontiersin.org, doi.org.

4. Babulic et al., Lactoferrin Binds through Its N-Terminus to the Receptor-Binding Domain of the SARS-CoV-2 Spike Protein, Pharmaceuticals, doi:10.3390/ph17081021.mdpi.com, doi.org.

5. Yathindranath et al., Lipid Nanoparticle-Based Inhibitors for SARS-CoV-2 Host Cell Infection, International Journal of Nanomedicine, doi:10.2147/IJN.S448005.dovepress.com, doi.org.

6. Alves et al., Inhibition of SARS-CoV-2 Infection in Vero Cells by Bovine Lactoferrin under Different Iron-Saturation States, Pharmaceuticals, doi:10.3390/ph16101352.mdpi.com, doi.org.

7. Kobayashi-Sakamoto et al., Bovine lactoferrin suppresses the cathepsin-dependent pathway of SARS-CoV-2 entry in vitro, International Dairy Journal, doi:10.1016/j.idairyj.2023.105805.sciencedirect.com, doi.org.

8. Andreu et al., Liposomal Lactoferrin Exerts Antiviral Activity against HCoV-229E and SARS-CoV-2 Pseudoviruses In Vitro, Viruses, doi:10.3390/v15040972.mdpi.com, doi.org.

9. Yazawa et al., Evaluation of SARS-CoV-2 isolation in cell culture from nasal/nasopharyngeal swabs or saliva specimens of patients with COVID-19, Research Square, doi:10.21203/rs.3.rs-2676422/v1.researchsquare.com, doi.org.

10. Piacentini et al., Lactoferrin Inhibition of the Complex Formation between ACE2 Receptor and SARS CoV-2 Recognition Binding Domain, International Journal of Molecular Sciences, doi:10.3390/ijms23105436.mdpi.com, doi.org.

11. Ostrov et al., Highly Specific Sigma Receptor Ligands Exhibit Anti-Viral Properties in SARS-CoV-2 Infected Cells, Pathogens, doi:10.3390/pathogens10111514.mdpi.com, doi.org.

12. Mirabelli et al., Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19, Proceedings of the National Academy of Sciences, doi:10.1073/pnas.2105815118.pnas.org, doi.org.

13. Salaris et al., Protective Effects of Lactoferrin against SARS-CoV-2 Infection In Vitro, Nutrients, doi:10.3390/nu13020328.mdpi.com, doi.org.

14. Berkowitz et al., Sigma Receptor Ligands Prevent COVID Mortality In Vivo: Implications for Future Therapeutics, International Journal of Molecular Sciences, doi:10.3390/ijms242115718.mdpi.com, doi.org.

Silva et al., 17 Oct 2024, USA, peer-reviewed, 24 authors.

This Paper Lactoferrin All

Immunomodulatory effect of bovine lactoferrin during SARS-CoV-2 infection

Andrea Marques Vieira Da Silva, Thiago Lazari Machado, Ryann De Souza Nascimento, Miguel Pires Medeiros Diniz Rodrigues, Felipe Soares Coelho, Luciana Neves Tubarão, Lorenna Carvalho Da Rosa, Camilla Bayma, Vanessa Pimenta Rocha, Ana Beatriz Teixeira Frederico, Jane Silva, Danielle Regina De Almeida De Brito E Cunha, Alessandro Fonseca De Souza, Raphaela Barbosa Gonçalves De Souza, Caroline Augusto Barros, Danielle Da Silva Fiscina, Luiz Claudio Pereira Ribeiro, Carlos Alberto Marques De Carvalho, Bruno Jorge Duque Da Silva, Rodrigo Muller, Tamiris Azamor, Juliana Gil Melgaço, Rafael Braga Gonçalves, Ana Paula Dinis Ano Bom

Frontiers in Immunology, doi:10.3389/fimmu.2024.1456634

Introduction: Lactoferrin (Lf) is an important immunomodulator in infections caused by different agents. During SARS-CoV-2 infection, Lf can hinder or prevent virus access to the intracellular environment. Severe cases of COVID-19 are related to increased production of cytokines, accompanied by a weak type 1 interferon response. Methods: We investigated the influence of bovine Lf (bLf) in the immune response during SARS-CoV-2 infection in vitro and in vivo assays. Results: Our results show a strong binding between bLf and TLR4/NF-kB in silico, as well as an increase in mRNA expression of these genes in peripheral blood mononuclear cells (PBMCs) treated with bLf. Furthermore, the treatment increased TLR4/TLR9 mRNA expression in infected K18-hACE2 mouse blood, indicating an activation of innate response. Our results show that, when bLf was added, a reduction in the NK cell population was found, presenting a similar effect on PD-1 in TCD4 + and TCD8 + cells. In the culture supernatant of PBMCs from healthy participants, bLf decreased IL-6 levels and increased CCL5 in COVID-19 participants. In addition, K18-hACE2 mice infected and treated with bLf presented an increase of serum pro-inflammatory markers (GM-CSF/IL-1b/ Frontiers in Immunology frontiersin.org 01

Ethics statement The studies involving humans were approved by Institutional Review Board under certificate number 37079320. 4 Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Supplementary material The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2024.1456634/ full#supplementary-material

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Immunol.', 'published': {'date-parts': [[2024, 10, 17]]}}

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