The immunological role of lactoferrin in virus defense

Lactoferrin is a multifunctional protein with many immunological properties, with many studies showing great potential in combating viruses. It is highly present at the external surfaces of the body and is as gentle as it is effective against viruses.
In vitro, and in vivo human studies, show direct antiviral activity of Lactoferrin against enveloped and non-enveloped DNA and RNA viruses [1-3]. Lactoferrin inhibits the entry of the virus into the cell, either by direct binding or by blocking the corresponding receptor. In the studies, Lactoferrin was successful in combating CMV, Hepatitis, HIV, Herpes simplex, Rotavirus, Polio, Adenovirus and Mayaro viruses [4].
Highly effective anti-virus protection via various mechanisms:
  • Inhibition of infiltration:
  • Lactoferrin actsin the acute phase of infection by inhibiting the entry of the virus into the cell
  • Binding to the virus:
  • Lactoferrincan also bind directly to viruses and inhibit propagation. It does so by binding to the glycosaminoglycans and integrins of the virus, as well as to the cell receptors.
  • Degradation of viral RNA:
  • After the virus enters the cell, Lactoferrin can degrade viral RNA and DNA and thus prevent them from causing damage within the cell.
In addition, Lactoferrin can support other parts of the immune defences. It increases the activity of Natural Killer (NK) cells and stimulates the aggregation and adhesion of immune cells (neutrophil granulocytes) [5] and may help restrict the entry of the virus into host cells during infection.
Wide range of applications
The areas of application for Lactoferrin in the defence against viruses are many, whether in prevention, in the acute defence response, or in combination with other preparations. Lactoferrin has shown a synergistic effect in combination with antiviral drugs such as Zidovudine (HIV-1), Cidofovir (Cytomegalovirus), Acyclovir (Herpes simplex types 1 and 2) and Interferon and Ribavirin (Hepatitis C virus) [6-8].
Lactoferrin and COVID-19
A recent article by Kell et al. [9] examines in detail the extent to which Lactoferrin can help support in combating COVID-19. 
COVID-19 is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). It is known that Lactoferrin can interact with some of the cell receptors used by SARS-CoV-2. It is therefore conceivable that Lactoferrin can contribute to the prevention and treatment of a coronavirus infection.
The article explains that Lactoferrin can bind to heparan sulfate proteoglycans (HSPGs) and the transmembrane enzyme angiotensin converting enzymes 2 (ACE2). These are relevant receptor entry points used by coronaviruses. 
These molecules represent a kind of anchoring site on the surface of the cell and help the virus to establish the first contact [1,10]. SARS-CoV then moves along the cell membrane, searching for specific entry ports, finally getting into the cell [1]. HSPGs can be either membrane-bound, in secretory vesicles or in the extracellular matrix. It has been shown that Lactoferrin can prevent the entry of some viruses by binding to HSPGs [11].
Although HSPGs are not alone in allowing SARS-CoV to actually penetrate the cell, they play an important role in the process of cell entry [1].
SARS-CoV finally penetrates the host cell via the ACE2 receptor [12]. ACE2 is strongly expressed in human lung cells, enterocytes of the small intestine and in the tubular cells of the kidney [1]. How exactly this process works requires further research, but Lactoferrin’s ability to block specific receptors means they are no longer available for the virus [13,14] playing an important role in the immunity of the host [15].
Occupying these receptors is an important property of Lactoferrin.  It can also help in preventing thrombocytopenia and hypercoagulation, both notable features of COVID-19 infection.
COVID-19 infection, like other infections, can trigger an excessive inflammatory reaction known as a cytokine storm [16]. This leads to excessive activation of the thrombocytes (platelets) which can cause thrombocytopenia. Thrombocytopenia is associated with an increased risk of severe disease progression and mortality in patients with COVID-19 [17,18].
Many COVID-19 patients develop Acute Respiratory Distress Syndrome (ARDS), which leads to pulmonary oedema and respiratory failure. Liver, heart & kidney damage can also follow. These scenarios are associated with excessive inflammatory messenger substances in the blood, characteristic of the cytokine storm [16,19]. 
Kell et al. conclude that Lactoferrin may play a therapeutic role in a COVID-19 infection, not only in the containment of a possible cytokine storm, but also by binding to the receptors and HSPGs. Lactoferrin could also prevent the accumulation of viruses in the host cell, as well as preventing the penetration of the virus via the host ACE2 receptors.