Immunomodulatory effect of bovine lactoferrin during SARS-CoV-2 infection
Andréa Marques Vieira da Silva, Thiago Lazari Machado, Raphaela Delmondes do Nascimento, Miguel Tréfaut Rodrigues, Felipe Soares Coelho, Luciana Tubarão, L. De Rosa, Camilla Bayma, Vanessa Pimenta Rocha, Ana Frederico, Jane da Silva, Danielle Brito e Cunha, Alessandro Pereira de Souza, Raphaela Barbosa Gonçalves de Souza, Caroline A. Barros, Danielle da Silva Fiscina, Luiz Cláudio Pereira Ribeiro, Carlos Alberto Marques de Carvalho, Bruno Jorge Duque da Silva, Rodrigo Müller, Tamiris Azamor, Juliana Gil Melgaço, Rafael Braga Gonçalves, Ana Paula Dinis Ano Bom
Abstract
Introduction 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. Methods We investigated the influence of bovine Lf (bLf) in the immune response during SARS-CoV-2 infection in vitro and in vivo assays. Results Our results show a strong binding between bLf and TLR4/NF-κB in silico , as well as an increase in mRNA expression of these genes in peripheral blood mononuclear cells (PBMCs) treated with bLf. Furthermore, the treatment increased TLR4/TLR9 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 + and TCD8 + 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 IL1B and IL6 in the lung tissue. Furthermore, bLf treatment was able to restore FTH1 levels in brain tissue. Discussion The data indicate that bLf can be part of a therapeutic strategy to promote the immunomodulation effect, leading to homeostasis during COVID-19.