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 (R2 > 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 KD 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.