Abstract: Lactoferrin binding to Sars-CoV-2 Spike glycoprotein protects host from infection, in ammation and iron dysregulation. Antimo Cutone University of Molise Department of Bioscience and Environment: Universita degli Studi del Molise Dipartimento di Bioscienze e Territorio Luigi Rosa Sapienza University of Rome Department of Public Health and Infectious Diseases Maria Carmela Bonaccorsi di Patti Sapienza University of Rome Department of Biochemical Sciences Federico Iacovelli Univ of Rome Tor Vergata Department of Biologyersity Maria Pia Conte Sapienza University of Rome Department of Public Health and Infectious Diseases Giusi Ianiro University of Molise Department of Bioscience and Territory: Universita degli Studi del Molise Dipartimento di Bioscienze e Territorio Alice Romeo University of Rome Tor Vergata Department of Biology Elena Campione University of Rome Tor Vergata Dermatology Unit Luca Bianchi University of Rome Tor Vergata Dermatology Unit Piera Valenti Sapienza University of Rome Department of Public Health and Infectious Diseases Mattia Falconi University of Rome Tor Vergata Department of Biology Giovanni Musci (  musci@unimol.it ) University of Molise Department of Bioscience and Territory: Universita degli Studi del Molise Dipartimento di Bioscienze e Territorio https://orcid.org/0000-0002-5196-709X Research Article Keywords: Lactoferrin, SARS-CoV-2, COVID-19, Iron homeostasis, In ammation Posted Date: May 17th, 2022 DOI: https://doi.org/10.21203/rs.3.rs-1605740/v1 License:   This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Lactoferrin binding to Sars-CoV-2 Spike glycoprotein protects host from infection, inflammation and iron dysregulation. Antimo Cutone1*, Luigi Rosa2*, Maria Carmela Bonaccorsi di Patti3, Federico Iacovelli4, Maria Pia Conte2, Giusi Ianiro1, Alice Romeo4, Elena Campione5, Luca Bianchi5, Piera Valenti2, Mattia Falconi4 and Giovanni Musci1# 1 Department of Biosciences and Territory, University of Molise, Pesche, Italy. 2 Department of Public Health and Infectious Diseases, Sapienza University of Rome, Italy. 3 Department of Biochemical Sciences, Sapienza University of Rome, Italy. 4 Department of Biology, University of Rome “Tor Vergata”, Rome, Italy. 5 Dermatology Unit, University of Rome “Tor Vergata”, Rome, Italy. * These authors equally contributed to the manuscript # Corresponding author: Giovanni Musci (musci@unimol.it). Keywords: Lactoferrin, SARS-CoV-2, COVID-19, Iron homeostasis, Inflammation 1 Abstract The anti-SARS-Cov-2 activity of the iron-binding protein Lactoferrrin has been investigated in epithelial and macrophagic cell models using a Pseudovirus decorated with the SARS-CoV-2 Spike glycoprotein. The human and, even more, the nutraceutically available bovine Lactoferrin inhibit pseudoviral infection in all cellular models tested. The bovine protein efficiently counteracts the deleterious effects of purified Spike on iron and inflammatory homeostasis, as shown by restored levels of the main proteins of the iron-handling system and, in the case of macrophagic THP-1 cells, of the proinflammatory cytokines IL-1β and IL-6. A direct interaction between Lactoferrin and Spike is likely at the basis of the observed effects, as demonstrated by an in vitro pull-down assay. Finally, in silico approaches have been applied to analyze the interactions of human and bovine Lactoferrins with Transferrin Receptor 1, a potential..