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 (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.
ABSTRACT
In 2020-2021, the world was engulfed by the pandemic of a new coronavirus infection (COVID-19) caused by the SARS-CoV-2 virus. The low population coverage with vaccination against COVID-19 and the lack of herd immunity result in the need to find an effective and safe etiotropic treatment. Medicinal agents for treatment of COVID-19, approved while preparing this publication, have several limitations related to the conditions of their use and/or population category. In this situation, interferon-containing drugs widely used in Russia and the CIS for prevention and treatment of viral infectious diseases, i.e. ARVI and influenza, may hold promise. This study aims to confirm in vitro antiviral activity against SARS-CoV-2 for the preparation VIFERON (R) containing recombinant human interferon alpha-2b (IFN alpha-2b). Materials and methods. Vero CCL-81 cells were infected with hCoV-19/StPetersburg-RII3524VR4/2020 strain of SARS-CoV-2 at doses of 10 TCID50 or 100 TCID50 per well. The suppressive effect of IFN alpha-2b, extracted from VIFERON (R) in dosage form of rectal suppositories, was evaluated by qRT-PCR at 24 h and 48 h after the infection of cells in two schemes, simulating preventive (24 h before infection) and therapeutic (2 h after infection) use of drugs. Results. IFN alpha-2b at concentrations of 800, 400, 200, 100 and 50 IU/ml, extracted from rectal suppositories of VIFERON (R), showed high biological activity, displayed as inhibition of SARS-CoV-2 strain replication in both infectious doses evaluated either at 24 h or at 48 h after cell infection. The "preventive" vs. "therapeutic" scheme was found to be more effective. In the "preventive" scheme the virus titre decreased by more than 3 lg TCID50 at 24 hours post-infection and by 5-6 lg TCID50 at 48 hours post-infection after administration of 800 IU/ml IFN alpha-2b. Conclusion. The study results evidence that VIFERON (R) in dosage form of rectal suppositories may be promising for prevention and treatment of new coronavirus infection in clinical practice.
ABSTRACT
A wide variety of zoonotic viruses that can cross the interspecies barrier promote the emergence of new, potentially pandemic viruses in the human population that is often accompanied by the disappearance of existing circulating strains. Among the various reasons underlying this phenomenon is the strengthening of herd immunity by expanding the immune layer of population and improving means and methods of medical care. However, natura abhorret vacuum, and new pathogens come to replace disappearing ones. Over the past ten years, humanity has faced two pandemics: swine flu A(H1N1)pdm09 in 2009 and COVID-19 in 2019, providing scientists with a unique opportunity to learn more about a relationship between respiratory viruses and their pathogenesis. Together with viruses of pandemic significance, a large number of seasonal respiratory viruses circulate, which contribute to the structure of human morbidity, and coinfections aggravate the condition of the illness. In the conditions of the spread of new viruses with unexplored characteristics, in the absence of means of prevention and therapy, it is especially important to prevent the aggravation of morbidity due to mixed infections. Here we review the mutual involvement of pandemic influenza A(H1N1)pdm09 and SARS-CoV-2 coronavirus and seasonal respiratory viruses in the epidemic process, discuss some issues related to their spread, potential causes affecting the spread and severity of the morbidity. The given facts testify to the existence of seasonality and temporal patterns of the beginning and end of respiratory viruses circulation. Interestingly, the beginning of circulation of the pandemic influenza A(H1N1)pdm09 virus led to a shift in the timing and intensity of circulation of some respiratory viruses, which is probably caused by existence of “replication conflicts” between them, and did not affect others. Coinfection with SARS-CoV-2-19 and other respiratory viruses, especially respiratory syncytial virus and rhinoviruses, was quite often observed. At the current stage, no aggravating effect of influenza on the course of COVID-19 in mixed infection has been established. Whether this is due to the mild course of influenza infection in the 2020 epidemic season, or the competitive impact of SARS-CoV-2 on influenza viruses is not yet clear. Experts are still at the stage of accumulating facts and working on creating means of effective prevention and treatment of the new coronavirus infection. © 2021 Saint Petersburg Pasteur Institute. All rights reserved.