The role of iron in the pathogenesis of COVID-19 and possible treatment with lactoferrin and other iron chelators

Abstract

Iron overload is increasingly implicated as a contributor to the pathogenesis of COVID-19. Indeed, several of the manifestations of COVID-19, such as inflammation, hypercoagulation, hyperferritinemia, and immune dysfunction are also reminiscent of iron overload. Although iron is essential for all living cells, free unbound iron, resulting from iron dysregulation and overload, is very reactive and potentially toxic due to its role in the generation of reactive oxygen species (ROS). ROS react with and damage cellular lipids, nucleic acids, and proteins, with consequent activation of either acute or chronic inflammatory processes implicated in multiple clinical conditions. Moreover, iron-catalyzed lipid damage exerts a direct causative effect on the newly discovered nonapoptotic cell death known as ferroptosis. Unlike apoptosis, ferroptosis is immunogenic and not only leads to amplified cell death but also promotes a series of reactions associated with inflammation. Iron chelators are generally safe and are proven to protect patients in clinical conditions characterized by iron overload. There is also an abundance of evidence that iron chelators possess antiviral activities. Furthermore, the naturally occurring iron chelator lactoferrin (Lf) exerts immunomodulatory as well as anti-inflammatory effects and can bind to several receptors used by coronaviruses thereby blocking their entry into host cells. Iron chelators may consequently be of high therapeutic value during the present COVID-19 pandemic.

Keywords: Blood groups; COVID-19; Free iron; Hemoglobin damage; Hypercoagulation; Hyperferritinemia; Inflammation; Iron chelators; Iron overload; Lactoferrin.

Graphical abstract

Fig. 1

(a) Structure of lactoferrin in holo-form (iron-saturated); (b) Structure of lactoferrin in apo-form (iron-free); and (c) Lactoferrin iron-binding site: two tyrosine (Y92 and Y192), one aspartic acid (D60), one histidine (H253) and one carbonate anion together with the arginine residue (R121). Modeled using Chimera software (http://www.cgl.ucsf.edu/chimera/). And PDB id 1BLF.

Fig. 2

A model of coronavirus cell entry and the protective role of lactoferrin in coronavirus infection. A: Lf blocks the infection of coronavirus by binding to HSPGs. Lactoferrin expression may be up-regulated when the coronavirus infects the human body. Lactoferrin locates to cell-surface HSPGs and prevents the preliminary interaction between the virus and host cells and the subsequent internalization process. B HSPGs play an important role in the process of coronavirus cell entry. The anchoring sites provided by HSPGs permit initial contact between coronavirus and host cells and the concentration of virus particles on the cell surface. Coronavirus rolls onto the cell membrane by binding to HSPGs and scans for specific entry receptors (ACEII), which leads to subsequent cell entry.

Fig. 3

Iron chelator structures.

Fig. 4

Mechanism of action of iron chelators.