Iron and iron-related proteins in COVID-19

Abstract

COVID-19 can cause detrimental effects on health. Vaccines have helped in reducing disease severity and transmission but their long-term effects on health and effectiveness against future viral variants remain unknown. COVID-19 pathogenesis involves alteration in iron homeostasis. Thus, a contextual understanding of iron-related parameters would be very valuable for disease prognosis and therapeutics.Accordingly, we reviewed the status of iron and iron-related proteins in COVID-19. Iron-associated alterations in COVID-19 reported hitherto include anemia of inflammation, low levels of serum iron (hypoferremia), transferrin and transferrin saturation, and high levels of serum ferritin (hyperferritinemia), hepcidin, lipocalin-2, catalytic iron, and soluble transferrin receptor (in ICU patients). Hemoglobin levels can be low or normal, and compromised hemoglobin function has been proposed. Membrane-bound transferrin receptor may facilitate viral entry, so it acts as a potential target for antiviral therapy. Lactoferrin can provide natural defense by preventing viral entry and/or inhibiting viral replication. Serum iron and ferritin levels can predict COVID-19-related hospitalization, severity, and mortality. Serum hepcidin and ferritin/transferrin ratio can predict COVID-19 severity. Here, serum levels of these iron-related parameters are provided, caveats of iron chelation for therapy are discussed and the interplay of these iron-related parameters in COVID-19 is explained.This synopsis is crucial as it clearly presents the iron picture of COVID-19. The information may assist in disease prognosis and/or in formulating iron-related adjunctive strategies that can help reduce infection/inflammation and better manage COVID-19 caused by future variants. Indeed, the current picture will augment as more is revealed about these iron-related parameters in COVID-19.

Molecular mimicry of the receptor-binding domain of the SARS-CoV-2 spike protein: from the interaction of spike-specific antibodies with transferrin and lactoferrin to the antiviral effects of human recombinant lactoferrin

“…High concentrations of anti-Tf in autoimmune pathologies lead to dysregulation of iron metabolism, including increased levels of serum iron, Tf, ferritin, iron saturation of Tf and total serum iron-binding capacity (Alyanakian et al 2007 ; Forni et al 2008 ). Few of these symptoms coincide with dysregulations of iron metabolism observed in the COVID-19 patients (Suriawinata and Mehta 2022 ), which can be explained by much lower level of Tf-cross-reactive antibodies induced by SARS-CoV-2 infection, as compared with anti-Tf serum level in those case-report studies. However, an increase of Tf expression induced by SARS-CoV-2 infection was described (McLaughlin et al 2020 ), which probably increased the risk of hypercoagulation (Tang et al 2020b ).…”

“…On the one side, if TfR is the critical receptor for SARS-CoV-2, its natural ligand, namely Lf, seems to be a promising competitor of coronavirus cell entry; on the other side, cross-reactivity of antibodies against RBD of Spike protein with Tf and Lf can provoke severe symptoms of COVID-19 accompanied by an autoimmune response against Lf and Tf. Considering that replication cycle of SARS-CoV-2 mediated by TfR1 endocytosis can alter normal Tf-mediated influx of iron, it is not surprising that COVID-19-associated dysregulations of iron and oxygen metabolism, such as low levels of serum iron and erythropoietin accompanied by high levels of ferritin and hepcidin, can be corrected by Lf (Suriawinata and Mehta 2022 ). Anti-anemic and anti-hypoxic effects of Lf associated with down-regulation of IL-6 and hepcidin (Cutone et al 2014 ; Rosa et al 2017 ; Lepanto et al 2019 ; Artym et al 2021 ) and up-regulation of erythropoietin and ceruloplasmin (Pulina et al 2010 ; Zakharova et al 2012 , 2018 ; Bonaccorsi di Patti et al 2018 ; Kostevich et al 2016 ; Sokolov et al 2022b ) seem to be a promising strategy for treating COVID-19 complications.…”

“…The studies on the design of SARS-CoV-2 antivirals are complicated by the presence of multiple receptors on a host cell surface that the virus uses to enter the cell, such as angiotensin-converting enzyme 2 (ACE2), neuropilin-1, CD147, tyrosine-protein kinase receptor UFO (AXL) and other co-receptors (Scialo et al 2020 ; Shang et al 2020 ; Zhang et al 2020 ; Wang et al 2020a , 2021 ; Wei et al 2020 ; Daly et al 2020 ; Cantuti-Castelvetri et al 2020 ; Jackson et al 2022 ). Dysregulation of iron metabolism in SARS-CoV-2-infected patients, which is associated with onset of hypoxia, inflammation, and the response to oxidative stress has been widely reviewed (Cavezzi et al 2022 ; Naidu et al 2022 ; Kronstein-Wiedemann et al 2022 ; Suriawinata and Mehta 2022 ). In this regard, the therapeutic potential of lactoferrin (Lf), a cationic homologue of serum transferrin (Tf), has been widely discussed as a regulator of inflammation, iron metabolism, tolerance to hypoxia and oxidative stress.…”

“…In this regard, the therapeutic potential of lactoferrin (Lf), a cationic homologue of serum transferrin (Tf), has been widely discussed as a regulator of inflammation, iron metabolism, tolerance to hypoxia and oxidative stress. Suriawinata and Mehta ( 2022 ) first discussed SARS-CoV-2-related dysregulations of iron metabolism in view of the transferrin receptor (TfR1) involvement in the infection (Tang et al 2020a , b ). Interestingly, the severity of COVID-19 is shadowed by the level of ferritin (Suriawinata and Mehta 2022 ), the heavy-chain form of which also interacts with TfR1.…”

“…Suriawinata and Mehta ( 2022 ) first discussed SARS-CoV-2-related dysregulations of iron metabolism in view of the transferrin receptor (TfR1) involvement in the infection (Tang et al 2020a , b ). Interestingly, the severity of COVID-19 is shadowed by the level of ferritin (Suriawinata and Mehta 2022 ), the heavy-chain form of which also interacts with TfR1. However, the binding site for ferritin is different from that for Tf (Sakamoto et al 2015 ).…”