Heparin‐interacting sites of bovine lactoferrin are involved in anti‐adenovirus activity

Abstract

Lactoferrin, a member of the transferrin family of approximately 80 kDa, consists of a single polypeptide chain folded in two symmetric, globular lobes (N- and C-lobes), each able to bind one ferric ion. This glycoprotein, found in physiological fluids of mammals, plays an important role in immune regulation and in defense mechanisms against bacteria, fungi, parasites, and viruses. Although the antiviral activity of lactoferrin is one of the major biological functions of such protein, the mechanism of action is still under debate. We have investigated both the role of tryptic fragments of bovine lactoferrin and the mechanism of lactoferrin antiviral effect toward adenovirus infection in HEp-2 cells. The results obtained demonstrated that the anti-adenovirus activity of lactoferrin is mediated by the N-terminal half of the protein as the N-lobe was able to inhibit adenovirus infection, even if at lower extent than undigested lactoferrin, whereas C-lobe was ineffective. The results also showed that the anti-adenovirus action of lactoferrin and of its N-terminal peptide lactoferricin took place on virus attachment to cell membrane, mainly through competition for common glycosaminoglycan receptors. The data provide evidence that the anti-adenovirus activity of lactoferrin is mediated mainly by the cluster of positive charges at the N-terminus of whole molecule and that the N-terminal peptide lactoferricin alone is sufficient to prevent infection.

Adenoviruses Use Lactoferrin as a Bridge for CAR-Independent Binding to and Infection of Epithelial Cells

“…Thus, HLf promoted infection by Ad5 in cells that corresponded to the normal tropism of this virus. From previous work by others, it has been suggested that HLf inhibits Ad2 from infecting Hep2 cells (3,13). In these studies, however, the concentrations of HLf that were inhibitory (0.5 mg/ml abolished 50% of the cytopathic effect) were higher than those we found to promote Ad5 infection in HCE, A549, and Hep2 cells.…”

Bovine Lactoferricin Inhibits Basic Fibroblast Growth Factor- and Vascular Endothelial Growth Factor165-Induced Angiogenesis by Competing for Heparin-Like Binding Sites on Endothelial Cells

“…Our findings are also consistent with reports that LfcinB interferes with the ability of herpes simplex virus and adenovirus to infect cells by competing for heparan sulfate proteoglycans that function as viral attachment sites. 47,48 It is noteworthy that LfcinB showed a reduced capacity to bind to HUVECs that had been pretreated with PI-PLC to remove cell-surface GPI-anchored proteins. This finding leads us to suggest that glypican-1, a GPI-anchored heparan sulfate proteoglycan that is present on endothelial cells and potentiates VEGF 165 or bFGF binding to their respective receptors, 49,50 may function as a binding partner for LfcinB.…”

Effect of lactoferrin on enteric pathogens

“…However, there are no data evaluating the effect of lactoferrin on the human enteric caliciviruses (sopoviruses or noroviruses). Likewise there are data showing that lactoferrin prevents adenovirus replication [17] and that the antiviral activity is located in the N terminus [18,19]. However, these studies have focused on respiratory rather than enteric adenoviral serotypes.…”