AUTHOR=Silva Andrea Marques Vieira da , Machado Thiago Lazari , Nascimento Ryann de Souza , Rodrigues Miguel Pires Medeiros Diniz , Coelho Felipe Soares , Tubarão Luciana Neves , da Rosa Lorenna Carvalho , Bayma Camilla , Rocha Vanessa Pimenta , Frederico Ana Beatriz Teixeira , Silva Jane , Cunha Danielle Regina de Almeida de Brito e , de Souza Alessandro Fonseca , Souza Raphaela Barbosa Gonçalves de , Barros Caroline Augusto , Fiscina Danielle da Silva , Ribeiro Luiz Claudio Pereira , de Carvalho Carlos Alberto Marques , da Silva Bruno Jorge Duque , Muller Rodrigo , Azamor Tamiris , Melgaço Juliana Gil , Gonçalves Rafael Braga , Ano Bom Ana Paula Dinis 

TITLE=Immunomodulatory effect of bovine lactoferrin during SARS-CoV-2 infection

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1456634

DOI=10.3389/fimmu.2024.1456634

ISSN=1664-3224

ABSTRACT=<sec><title>Introduction</title><p>Lactoferrin (Lf) is an important immunomodulator in infections caused by different agents. During SARS-CoV-2 infection, Lf can hinder or prevent virus access to the intracellular environment. Severe cases of COVID-19 are related to increased production of cytokines, accompanied by a weak type 1 interferon response.</p></sec><sec><title>Methods</title><p>We investigated the influence of bovine Lf (bLf) in the immune response during SARS-CoV-2 infection <italic>in vitro</italic> and <italic>in vivo</italic> assays.</p></sec><sec><title>Results</title><p>Our results show a strong binding between bLf and TLR4/NF-κB <italic>in silico</italic>, as well as an increase in mRNA expression of these genes in peripheral blood mononuclear cells (PBMCs) treated with bLf. Furthermore, the treatment increased <italic>TLR4/TLR9</italic> mRNA expression in infected K18-hACE2 mouse blood, indicating an activation of innate response. Our results show that, when bLf was added, a reduction in the NK cell population was found, presenting a similar effect on PD-1 in TCD4<sup>+</sup> and TCD8<sup>+</sup> cells. In the culture supernatant of PBMCs from healthy participants, bLf decreased IL-6 levels and increased CCL5 in COVID-19 participants. In addition, K18-hACE2 mice infected and treated with bLf presented an increase of serum pro-inflammatory markers (GM-CSF/IL-1β/IL-2) and upregulated mRNA expression of <italic>IL1B</italic> and <italic>IL6</italic> in the lung tissue. Furthermore, bLf treatment was able to restore <italic>FTH1</italic> levels in brain tissue.</p></sec><sec><title>Discussion</title><p>The data indicate that bLf can be part of a therapeutic strategy to promote the immunomodulation effect, leading to homeostasis during COVID-19.</p></sec>