Lactoferrin, Iron Metabolism and Coronavirus

By mivision.com.au

Lactoferrin is a glycoprotein of human secretions and part of the non-specific, or innate immune system, it has been used in trials in Italy on patients affected by Covid-19 as adjunct therapy and seems that has worked pretty well; the patients resolved in the arch of few days and it looks that they are also suggesting as preventive therapy.

The doctor in charge was explaining that the idea of testing lactoferrin came to her while brainstorming on why kids are almost immune to this virus, or if affected in less dramatic forms (other than those with the Kawasaki disease manifestation I would add), and since lactoferrin seems to be a protein under studies of these last periods she started trials on Covid-19 patients and the results were satisfactory.

A review from Italian scientists analyzes the functions and implications of lactoferrin with viral infections and the iron metabolism associate. The article has been published on the “International Journal of Molecular Science” and includes scientists from the University of Rome, Italy, department of Medicine and Infectious Diseases, Tor Vergata, and La Sapienza.

The authors in this review analyze the properties of lactoferrin and its interaction and function with Coronavirus infection and inflammation status, as natural barrier of both respiratory and gastrointestinal route of entry and of inflammation of the virus, and the role of reverting iron disorders caused by the viral colonization.

Under their description iron plays a critical role in the inflammatory processes by facilitating viral progression and exacerbating the inflammatory process at the same time. Iron in excess creates ROS, reactive oxygen species, free radicals which are oxidative and damaging and cause of organs failure among the other degenerative processes.

In pathological conditions the concentration of iron increases and so the susceptibility to infections, ROS production and inflammatory damage. Iron homeostasis includes different proteins like, transferrin, ferritin, and lactoferrin to mention the most common.

During viral infection, the homeostasis of iron is disturbed leading to iron disorders worsened by the action of inflammatory cytokines as interleukine-6, (IL-6), for example.

Studies done on patients affected by viral infections demonstrate that when serum levels of IL-6 increases, the iron saturation of serum levels of transferrin as well as of the receptors decreases; this shows that the host’s status of iron can alter the course of infection and its resolution, in fact significant viral replication requires high iron availability. Clinical data supports that iron homeostasis disorders and dysregulated synthesis brings to intercellular overload of iron which facilitate viral multiplication and spreading of the infection.

Iron imbalance induced by SARS-CoV-2 infection and related inflammatory processes could play a role in the activation and progression of organ impairment. Indeed, the most severe cases of Covid-19, present massive systemic level of infection and inflammatory markers as cytokines and tumor necrosis factor (TNF-a). The excessive release of pro-inflammatory biomarkers referred as “cytokines storm” has evolved as an important system of surveillance to fight infections and inflammations but that may contribute to organ damage and impairment.

Lactoferrin instead could be a key element as adjunct treatment of host defenses acting as protective barrier against the virus. It is already known that lactoferrin plays an important role against microbial and viral infections for its anti-inflammatory effects on mucosal surfaces and that is able to regulate the iron metabolism.

This protein is capable to chelate reversibly two Fe (III), or Fe trivalent per molecule with high affinity, it is a cationic glycoprotein, release iron at pH values lower than 5.5 and can bind trivalent iron until pH values of ~3. It is a protein of the innate immune system which is constitute by lymphocytes T and other type of cells and their products, secrets by exocrine glands and neutrophils during infections and inflammation.

Variety of studies have recognized a highest homology of sequence among human and bovine lactoferrin, ~70% and so of biological functions, for this reason has been applied in studies in vitro and vivo and recognized as “safe” by the Food and Drugs Administration (FDA) and available in large quantities.

By bio-quad.com

The various functions are associate to the capacity to chelate two trivalent iron, or ferric iron, or Fe (III) and to bind to anionic surfaces; with its anti-inflammatory and immunomodulatory properties is capable to control the production of pro-inflammatory cytokines as demonstrated in vitro as in vivo, as in clinical trials.

Several studies describe its antiviral activity towards enveloped and naked viruses of different families, as Retroviridae, Papillomaviridae, Herpesviridae, Adenoviridae, Pneumoviridae, and so on.

It has also been found to obstacle viral entry into host cells by binding competitively to cell surface receptors, mainly negatively charged compounds such as glycosaminoglycans (GAGs).

In general, the antiviral effect of lactoferrin occurs during the initial phase of infection by preventing the viral particle entrance into the host cells, either by blocking cellular receptors than binding viral particles.

For the majority of viruses tested, lactoferrin employs its activity by binding to heparan sulphate, while with few viruses interacting with other surface components.

The results of studies effectuated on mice cells- and which were investigating the role of lactoferrin at the entry of SARS pseudo viruses- revealed that this protein blocks the entry by binding to the spike protein of the virus, showing this way that its inhibitory activity takes place at the attachment viral stage.

The present accepted model suggests that lactoferrin could block viral entry by interacting with heparan sulfate proteoglycans, which mediate the transport of extracellular virus particles from the low affinity sites to the high affinity specific entry as ACE-2.

These results suggest that lactoferrin could play a protective role in host defense against SARS-CoV-2 and host cells. The ability to enter inside the nucleus may also reduce the activation of the cytokines storm avoiding systemic, lung, or intestinal iron homeostasis disorders as well as diseases exacerbation.

Recently have been also investigated the effects of lactoferrin in regulating the activation of plasminogen, to verify if this molecule is involved in controlling the coagulation cascade promoted by the coronavirus.

Current studies have shown that can exercise negative regulatory effects on cells migration via inhibition of prostaglandins activation and through the regulation of fibrinolysis. This activity has been also confirmed by evidence of a peptide with the amino acids sequence derived from lactoferrin showing antithrombotic activity.

The authors test that there are more than 140 trials available on trials.gov, among these, major contribution of lactoferrin has been demonstrated on anemia, bacterial and viral infection, in both communitarian and nosocomial inflammation and prevention of sepsis. These trials assess the safety, tolerability, and efficacy of lactoferrin as oral dietary supplements and/or as intranasal spray.  

It seems an alternative and adjuvant therapy to take in consideration since already applied in Italy and proved to function, eventually to add among the other alternative and validated therapies to the regular and current most utilized and verified therapies for Covid-19 in hospital and at home, for those who does not require hospitalization.

The data in this article have been summarized and rearranged from the original article written from Italian scientists with the exception of some of my personal comments and observations.

Thanks For Reading

Mariarosaria M.

References:

“Lactoferrin as Protective Natural Barrier of Respiratory and Intestinal Mucosa against Coronavirus Infection and Inflammation” International Journal of Molecular Medicine

Int. J. Mol. Sci. 2020

http://www.mdpi.com/journal/ijms

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s