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Lactoferrin Binding to SARS-CoV-2 Spike Glycoprotein Blocks Pseudoviral Entry and Relieves Iron Protein Dysregulation in Several In Vitro Models

SARS-CoV-2 causes COVID-19, a predominantly pulmonary disease characterized by a burst of pro-inflammatory cytokines and an increase in free iron. The viral glycoprotein Spike mediates fusion to the host cell membrane, but its role as a virulence factor is largely unknown. Recently, the antiviral ac...

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Detalles Bibliográficos
Autores principales: Cutone, Antimo, Rosa, Luigi, Bonaccorsi di Patti, Maria Carmela, Iacovelli, Federico, Conte, Maria Pia, Ianiro, Giusi, Romeo, Alice, Campione, Elena, Bianchi, Luca, Valenti, Piera, Falconi, Mattia, Musci, Giovanni
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9612385/
https://www.ncbi.nlm.nih.gov/pubmed/36297546
http://dx.doi.org/10.3390/pharmaceutics14102111
Descripción
Sumario:SARS-CoV-2 causes COVID-19, a predominantly pulmonary disease characterized by a burst of pro-inflammatory cytokines and an increase in free iron. The viral glycoprotein Spike mediates fusion to the host cell membrane, but its role as a virulence factor is largely unknown. Recently, the antiviral activity of lactoferrin against SARS-CoV-2 was demonstrated in vitro and shown to occur via binding to cell surface receptors, and its putative interaction with Spike was suggested by in silico analyses. We investigated the anti-SARS-CoV-2 activity of bovine and human lactoferrins in epithelial and macrophagic cells using a Spike-decorated pseudovirus. Lactoferrin inhibited pseudoviral fusion and counteracted the deleterious effects of Spike on iron and inflammatory homeostasis by restoring basal levels of iron-handling proteins and of proinflammatory cytokines IL-1β and IL-6. Using pull-down assays, we experimentally proved for the first time that lactoferrin binds to Spike, immediately suggesting a mechanism for the observed effects. The contribution of transferrin receptor 1 to Spike-mediated cell fusion was also experimentally demonstrated. In silico analyses showed that lactoferrin interacts with transferrin receptor 1, suggesting a multifaceted mechanism of action for lactoferrin. Our results give hope for the use of bovine lactoferrin, already available as a nutraceutical, as an adjuvant to standard therapies in COVID-19.