A new type of coronavirus infection (COVID-19), caused by SARS-CoV-2, is transmitted through respiratory droplets or saliva. High viral loads were detected, soon after symptom onset, in the oropharynx of ill patients, as well as in the asymptomatic subjects. The nasal and oral cavities are therefore directly associated with the transmission of SARS-CoV-2 and could represent the first target in infection control measures. Moreover, in most severe cases of infection, patients show massive systemic levels of pro-inflammatory cytokines, which lead to physiological deterioration and death. Well-timed control of the cytokine storm together with the reduction of lung inflammatory cell infiltration could be the key to improve treatment success as well as, the reduction of the mortality rate. Among several factors affecting viral infection and related inflammatory processes, iron homeostasis disorders play a critical role. In fact, it favors one side, viral progression, and on the other exacerbation inflammatory processes. Lactoferrin (Lf), a glycoprotein able to modulate iron and inflammatory homeostasis, could represent a promising tool able to target multi-faced aspects of the viral progression and pathogenesis. Lf possesses antiviral activity against enveloped and naked viruses by hindering viral entry into host cells through its competitive binding to the cell surface receptors and/or to the virus. This capability of Lf strengthens the idea that this glycoprotein is "an important brick in the mucosal wall, effective against viral attacks". Recently, the role of Lf in the entry of SARS pseudovirus into Myc cells has been investigated, and results obtained revealed that Lf was able to block the binding of the spike protein to host cells. Taken together, these results suggest that Lf could play a protective role in host defense against SARS-CoV-2 infection.
Covid-19 is spreading rapidly through the world and specific tools, to prevent and treat people who are sick, are very few. Significant efforts have been made to develop therapeutic interventions against SARS-CoV-2 infection, but for most of these, adverse effects have been observed. Therefore, we have to intensify the research in this field. While waiting for safe and effective vaccines, we have to explore safe treatments to prevent the early phase of infection of SARS-CoV-2, its replication and spread, and to shorten the time required to negativize patients showing positivity to SARS-CoV-2. Among existing drugs, we had identified bovine lactoferrin as a good candidate that could be an effective treatment in decreasing viral shedding and subsequent transmission. BLf possesses pivotal biological activities, such as antiviral, anti-inflammatory, and immunomodulatory ones. Furthermore, bLf is available in large quantities, in different commercial formulations and is generally recognized as safe (GRAS) by the Food and Drug Administration (FDA). Diverse lactoferrin based products exhibit beneficial health properties. Biosoluble tablets of bLf are used in the treatment of chronic inflammation of the oral cavity (1). Aerosolized bovine lactoferrin counteracts infection, inflammation, and iron dysbalance in a cystic fibrosis mouse model (2). BLf is now administered intranasally and orally in several clinical trials, in order to hinder SARS-CoV-2 infection. Lang and colleagues revealed that Lf was able to block the entry of SARS pseudovirus into Myc cells, indicating that Lf exerted its inhibitory function at the viral attachment stage (3). Therefore, Lf could represent a promising tool able to exert simultaneously multiple functions. As a matter of fact, bLf by inhibiting viral infection and progression as well as inflammatory processes induced by SARS-Co-2 could be able to restore also iron homeostasis disorders. Iron homeostasis disorders include Fpn, TfR1, and Ftn dysregulated synthesis leading to an intracellular iron overload which facilitates viral multiplication and spreading. The possible restoration of the correct homeostasis of iron by bLf, in infected monolayers, could offer, in vitro models, a demonstration of the efficacy of this protein in treating COVID-19. In particular, the Blf mechanism favoring viral infection, replication, and spread, without any adverse effect.
The aim of our proposal is to test if bLf, without any adverse effect, could be able to block the entry and intracellular multiplication of SARS-CoV-2 and if it can inhibit inflammatory processes and counteract iron dysregulation provoked by viral infection.
1-Takahashi Y et al. Int J Pharm doi: 10.1016/j.ijpharm.2007.05.032 (2007)
2-Cutone A et al. Int J Mol Sci. doi: 10.3390/ijms20092128 (2019)
3-Lang, J. et al. PLoS One doi: 10.1371/journal.pone.0023710 (2011)