The Biology of Lactoferrin, an Iron-Binding Protein That Can Help Defend Against Viruses and Bacteria

Douglas B Kell, Eugene L Heyden, Etheresia Pretorius, Douglas B Kell, Eugene L Heyden, Etheresia Pretorius

Abstract

Lactoferrin is a nutrient classically found in mammalian milk. It binds iron and is transferred via a variety of receptors into and between cells, serum, bile, and cerebrospinal fluid. It has important immunological properties, and is both antibacterial and antiviral. In particular, there is evidence that it can bind to at least some of the receptors used by coronaviruses and thereby block their entry. Of importance are Heparan Sulfate Proteoglycans (HSPGs) and the host receptor angiotensin-converting enzyme 2 (ACE2), as based on other activities lactoferrin might prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from attaching to the host cells. Lactoferrin (and more specifically enteric-coated LF because of increased bioavailability) may consequently be of preventive and therapeutic value during the present COVID-19 pandemic.

Keywords: HSPGs; coronaviruses; iron; lactoferrin; membrane receptors.

Copyright © 2020 Kell, Heyden and Pretorius.

Figures

Figure 1
Figure 1
Overview of this review of lactoferrin (LF). We discuss (1) discovery and structure of LF; (2) LF membrane receptors and some of the bacteria, their products and viruses that might also bind to these receptors, (3) including how acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (causing COVID-19) may interact with host cells (see Figure 6 and Conclusion for a detailed discussion); (4) and how LF assists with host immunity. Diagram created with BioRender (www.biorender.com).
Figure 2
Figure 2
Crystal structures of bovine lactoferrin (PDB code = 1BLF), human lactoferrin (1B0L), and rabbit serum transferrin (1JNF). Adapted from Vogel (10). Pink spheres represent ferric iron (Fe3+) binding sites.
Figure 3
Figure 3
Bacterial binding to various receptors, e.g., Toll-like receptors 2 and 4 (TLR2 and 4), as well as complement receptors, leads to protein arginine deiminase 4 (PAD4) activation, followed by chromatin decondensation, hypercitrullination of histones 3 and 4 in the nucleus, and nuclear membrane disruption. Granules also release lactoferrin. Neutrophil Extracellular Traps (NETs) and their protein constituents (including lactoferrin) are released from the neutrophil. Adapted from Jorch and Kubes (142) and Law and Gray (143). Bacteria are expelled and trapped in the NETs. Diagram created with BioRender (https://biorender.com/).
Figure 4
Figure 4
Ways by which bacteria acquire iron [adapted from (19, 30)]. Transferrin receptor, lactoferrin receptor, hemophore (Hp), hemophore receptor, and hemopexin. Siderophores remove iron from lactoferrin, ferritin and transferrin, and also from the environment. Stealth siderophores are modified in such a way as to prevent siderocalin binding. A primary bacterial defense against siderocalin involves the production of stealth siderophores. Modified from Rosa et al. and Skaar (19, 30). Diagram created with BioRender (https://biorender.com/).
Figure 5
Figure 5
Simplified platelet signaling and receptor activation during disease with main dysregulated molecules thrombin, fibrin(ogen), von Willebrand Factor (vWF) interleukins (IL) like IL-1α, IL-1β, and IL17A and cytokines like TNF-α. Diagram created with BioRender (https://biorender.com/).
Figure 6
Figure 6
Possible action of (1) lactoferrin by occupying binding sites of (2) SARS-CoV-2 that causes COVID-19. (3) Entry into host cells occur when SARS-CoV-2 first attaches to Heparan sulfate proteoglycans (HSPGs). This attachment initiates the first contact between the cell and the virus, concentrating the virus on the cell surface, (4) followed attaching of the virus to the host receptor (ACE2) and association and entering are then facilitated via clathrin-coated pits (5) Virus replication can then happen inside the cell. (6) One of the characteristics of Lactoferrin, is that it attaches to HSPGs. (7) Currently we do not know if ACE2 is also a receptor for lactoferrin. (8) Lactoferrin may block the entry of SARS-CoV-2 into the host cell, by occupying HPSGs, thereby preventing SARS-CoV-2 initial attachment and accumulation on the host cell membrane. COVID-19 infection template adjusted from www.biorender.com.

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