Anti‐HSV activity of lactoferrin and lactoferricin is dependent on the presence of heparan sulphate at the cell surface

Abstract

Lactoferrin (LF) is a multifunctional glycoprotein, which plays an important role in immune regulation and defense mechanisms against bacteria, fungi, and viruses. Lactoferricin (Lfcin) is a potent antimicrobial peptide generated from the N-terminal part of LF by pepsin cleavage. In this study, we investigated the mechanisms of the anti-herpes simplex virus (anti-HSV) activity of LF and Lfcin. The results demonstrated that LF and Lfcin inhibited the entry of HSV into Vero cells. LF had no effect against HSV after the virus had entered the cells, while Lfcin exerted antiviral activity also after the initial binding of the virus to the host cell. The distribution of LF and Lfcin in the cells was investigated by immunogold-labeling and transmission electron microscope (TEM). LF was found mainly at the cell surface in cells expressing heparan sulphate. Lfcin was randomly distributed intracellularly. LF must be present at the cell surface to exert antiviral activity, while Lfcin exert its antiviral activity also when found mainly intracellularly. Both LF and Lfcin were dependent on the presence of heparan sulphate at the cell surface to exert their antiviral activity.

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.…”

Milk Derived Peptides with Immune Stimulating Antiviral Properties

“…Herpes simplex virus 1 human and bovine lactoferrin and lactoferricin, lactoperoxidase Binding to both virus particle and cellular receptors (heparan sulphate) to prevent viral adsorption and entry; Interference with intracellular replication events or synthesis of progeny viral components [9,35,55,[77][78][79][81][82][83] chemically modified milk proteins e.g. serum albumin, -lactalbumin, -lactoglobulin [89,93,99,100] Herpes simplex virus 2 human and bovine lactoferrin…”

“…Similarly, both apo-and holo-lactoferrin has been demonstrated to interact both with canine herpes virus and surface receptors on the Madin-Darby canine kidney cells, thus inhibiting canine herpes virus infection [74]. With regard to the anti-herpes simplex virus 1 ability of lactoferrin, both bovine and human lactoferrin and lactoferricin have demonstrated the ability to block viral entry and also inhibit viral cell-to-cell spread in a dose dependent manner [55,[77][78][79], through interaction with negatively charged glycosaminoglycans like heparan sulphate on the cell surface [55,[80][81][82][83] and elements of the viral particle [55]. Differently from herpes simplex virus 1, Marchetti et.…”

“…Many of the traditional entry blocking effects observed by lactoferrin involve electrostatic interaction with anionic heparan sulphate molecules on the host cell surface [82]. The ability to interact with anionic heparan sulphate is maybe not that surprising, when evaluating the three dimensional structural composition of lactoferrin, demonstrating a rather striking cationic patch on the N-terminal lobe of the molecule [84] (Figure 1).…”

Antimicrobial peptides: mode of action and perspectives of practical application

“…При этом меллитин имеет повышенное сродство к гепарансульфату, что подтверждено данными изотермического калориметрического титрования [68]. Лактоферрин и его аналоги также проявляют высокое сродство к гепарансульфату [69]. Клетки, обработанные аналогами лактоферрина, менее подвержены заражению ВГП, нежели необработанные клетки, в то время как обработка этими пептидами суспензии ВГП не приводила к ингибированию вируса [69].…”