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

Abstract

The pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection involves dysregulations of iron metabolism, and although the mechanism of this pathology is not yet fully understood, correction of iron metabolism pathways seems a promising pharmacological target. The previously observed effect of inhibiting SARS-CoV-2 infection by ferristatin II, an inducer of transferrin receptor 1 (TfR1) degradation, prompted the study of competition between Spike protein and TfR1 ligands, especially lactoferrin (Lf) and transferrin (Tf). We hypothesized molecular mimicry of Spike protein as cross-reactivity of Spike-specific antibodies with Tf and Lf. Thus, strong positive correlations (R 2 > 0.95) were found between the level of Spike-specific IgG antibodies present in serum samples of COVID-19-recovered and Sputnik V-vaccinated individuals and their Tf-binding activity assayed with peroxidase-labeled anti-Tf. In addition, we observed cross-reactivity of Lf-specific murine monoclonal antibody (mAb) towards the SARS-CoV-2 Spike protein. On the other hand, the interaction of mAbs produced to the receptor-binding domain (RBD) of the Spike protein with recombinant RBD protein was disrupted by Tf, Lf, soluble TfR1, anti-TfR1 aptamer, as well as by peptides RGD and GHAIYPRH. Furthermore, direct interaction of RBD protein with Lf, but not Tf, was observed, with affinity of binding estimated by K D to be 23 nM and 16 nM for apo-Lf and holo-Lf, respectively. Treatment of Vero E6 cells with apo-Lf and holo-Lf (1–4 mg/mL) significantly inhibited SARS-CoV-2 replication of both Wuhan and Delta lineages. Protective effects of Lf on different arms of SARS-CoV-2-induced pathogenesis and possible consequences of cross-reactivity of Spike-specific antibodies are discussed. Supplementary Information The online version contains supplementary material available at 10.1007/s10534-022-00458-6.

Inhibition of SARS-CoV-2 Infection in Vero Cells by Bovine Lactoferrin under Different Iron-Saturation States

“…This finding is in line with a recent study showing that 1 mg/mL apo-or holo-hLf derived from the milk of transgenic goats promoted a similar pronounced reduction in the titers of SARS-CoV-2 ancestral and delta strains during infection of Vero E6 cells [30]. Since our data revealed that SARS-CoV-2 ancestral and omicron strains were also equivalent in terms of sensitivity to apo-or holo-bLf during infection, the ancestral one was selected for the next experiments as a precautionary measure due to its lower risk of community spread.…”

Liposomal Lactoferrin Exerts Antiviral Activity against HCoV-229E and SARS-CoV-2 Pseudoviruses In Vitro

“…In addition, as Lf is reported to attach to the ACE2 cell receptor used by SARS-CoV-2 to enter the cell, the components of the liposome may induce protein changes in cellular TMPRSS2, which is also involved in the entry of this virus [15]. The mechanism of action of Lf against SARS-CoV-2 is also explained by its direct interaction with the receptor binding domain (RBD) of the Spike protein [30,31] and its binding to heparan sulfate proteoglycans, thus preventing the early attachment phase [14]. In addition, some in silico studies showed that Lf also interacts with the transferrin receptor 1, which can be an alternative co-receptor for SARS-CoV-2 entry [31,32].…”

The role of ferroptosis in virus infections

“…Certain viruses have been found to hijack cellular TFR1 and promote virus internalization and by clathrin-mediated endocytosis. For example, TFR1 was shown to be a vital protein in promoting the entry of SARS-CoV-2 facilitating virus endocytosis (Sokolov et al, 2023). As a potential therapeutic target, TFR1 exhibits the effect of inhibiting SARS-CoV-2 infections by chemical inhibitors (such as ferristatin II) (Sokolov et al, 2022;.…”